Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is the most common degenerative disease of the motor neuron system. The disorder is named for its underlying pathophysiology, with “amyotrophy” referring to the atrophy of muscle fibers, which are denervated as their corresponding anterior horn cells degenerate. “Lateral sclerosis” refers to the changes seen in the lateral columns of the spinal cord as the upper motor neuron (UMN) axons in these areas degenerate and are replaced by fibrous astrocytes (gliosis).

ALS is a fatal disease, with a median survival period of 3 years from onset of weakness.[4] (See Prognosis.) Aspiration pneumonia and medical complications of immobility contribute to morbidity in most patients with the disease.

ALS was first described in 1869 by the French neurologist Jean-Martin Charcot and hence is also known as Charcot disease; however, it gained popular recognition and its best-known eponym in the United States after the baseball player Lou Gehrig announced his diagnosis with the disease in 1939.[5, 6, 7, 8, 9] ALS is also known as motor neuron disease (MND).

It has long been held, that “the cause of ALS is unknown." This stark statement needs to be retired, as it shuts the door on recognizing how much is actually known about ALS pathogenesis. It is more correct to say, today, that we have a fairly good understanding of how ALS gets started and how it evolves. We no longer think in terms of a single cause for initiation of the disease, but rather in terms of multiple potential causes and pathways. (See Disease Pathogenesis.)

Most contemporary research focuses on unveiling the downstream “final common pathway” mechanisms thatlead to cell death, hoping to find ways of interfering with these “downstream” mechanisms and extending patient survival.

Two exceptions are the study of the role of mutant SOD1 in generating and propagating ALS within the motor systems of carriers of an SOD1 gene and the study of the role of misfolded TDP-43 in spreading disease in the motor systems of carriers and most non-carriers of TDP-43 mutations, including all sporadic cases.

In familial ALS due to an SOD1 mutation, the altered gene product is (1) the agent of spread of the disease in the motor network and (2) its accumulation and aggregation in motor neurons leads to their demise. An intrathecal treatment (tofersen) that interferes with production of mSOD1 has been developed and approved for treatment of this form of familial ALS [REF as above].

In contrast, TDP-43 is a nuclear-to-cytoplasmic mRNA transporter protein that misfolds and precipitates in the motor neuronal cytoplasm of patients with sporadic ALS /FTLD and most cases of familial ALS/ FTLD, including but not limited to those inheriting a mutated TDP-43 gene. Abnormal misfolded TDP-43 derived from precipitate of familial (TDP-43 mutant) or sporadic FTLD cases can spread within the motor neuronal  system.[204]

Degenerative effects of ALS

ALS is one of the system degeneration diseases, disorders that cause networks that work together in health to disintegrate together in an organized manner.[15, 16] ALS results from the systematic dismantling of the motor neuron system, with the clinical manifestations in each patient deriving from the site of onset and cell type involved; the relative affinity of the dismantling process for prefrontal, upper and lower motor neurons; and the rate of the disease’s spread within the network.[17]

In its classic form, ALS affects motor neurons at 2 or more levels of the motor neuron network supplying multiple regions of the body. It affects lower motor neurons (LMNs) that reside in the anterior horn of the spinal cord and in the brain stem, corticospinal UMNs that reside in the precentral gyrus, and, frequently, prefrontal motor neurons that are involved in planning or orchestrating the work of the upper and lower motor neurons.[18] (See Pathophysiology.)

Loss of LMNs leads to progressive muscle weakness, wasting (atrophy), and fasciculations, with loss of reflexes and muscle tone. Loss of corticospinal UMNs usually leads to milder weakness associated with stiffness (spasticity), which may be severe, and abnormally brisk reflexes.

Loss of prefrontal neurons may result in special forms of cognitive impairment that include, most commonly, executive dysfunction but that may also include an altered awareness of social implications of one’s circumstances and, consequently, maladaptive social behaviors.[19] In its fully expressed forms, the prefrontal dysfunction meets established criteria for frontotemporal dementia.[20, 21] Loss of ability to integrate motor function (apraxia), a premotor function, is seen at times. It is more noticeable in limbs that are not overly weak.

Types of motor neuron disease

Classic ALS

The term classic ALS is reserved for the form of disease that involves upper and lower motor neurons. The classic form of sporadic ALS usually starts as dysfunction or weakness in one part of the body and spreads gradually within that part and then to the rest of the body.[22] Ventilatory failure results in death 3 years, on average, after the onset of focal weakness. The rate of disease progression varies widely, however, with some patients dying a few months after experiencing their first symptom and others still walking 10 years afterward.

Progressive muscular atrophy and flail limb syndrome

The disease may be restricted to LMNs. When the pattern of LMN involvement is asymmetrical, the disorder is termed progressive muscular atrophy (PMA).

Most patients with PMA have a course indistinguishable from that of patients with classic ALS (except for the absence of UMN findings).

Kim et al concluded that PMA should be considered a form of ALS.[156] Review of the medical records of 91 patients with PMA and 871 with ALS showed that patients with PMA were more likely to be male, to be older, and to live longer than those with ALS, but risk of death increased with age at onset in both patient groups and UMN signs developed in 22% of patients with PMA within 61 months after diagnosis.[156]

In the study, demographic and other clinical variables did not differ at diagnosis between patients who did or did not develop UMN signs. In PMA, as in ALS, the factors present at diagnosis that predicted shorter survival were greater number of body regions affected, lower FVC, and lower ALSFRS-R score.

Patients with a symmetrical pattern, called flail limb syndrome, have a course that may be far longer.[23, 71]

Primary lateral sclerosis

When only UMNs are involved, the disease is called primary lateral sclerosis (PLS). The course of PLS differs from that of ALS and is usually measured in decades.[24]  PLS should not be considered “a form of ALS,” and is a distinct entity.

Progressive bulbar palsy

Rarely, the disease is restricted to bulbar muscles, in which case it is called progressive bulbar palsy (PBP). In most patients who present with initial involvement of bulbar muscles, the disease evolves to classic ALS.

Familial ALS

Worldwide, a family history of ALS is obtained in about 5% of cases; these patients have familial ALS. Most familial ALS is inherited in an autosomal dominant pattern,[18] often with reduced penetrance, but other patterns, such as X-linked or autosomal recessive inheritance, are seen (see Etiology.)

The fact that in most patients ALS is sporadic does not preclude a genetic contribution to the disease in these cases. ALS as a whole is best thought of as a disease showing complex inheritance.

Complications

Complications of ALS can include the following:

• Progressive inability to perform activities of daily living (ADLs), including handling utensils for self feeding

• Deterioration of ambulation

• Aspiration pneumonia

• Respiratory insufficiency

• Complications from being wheelchair-bound or bedridden, including decubitus ulcers and skin infections (while rare in patients with ALS, these complications can emerge if appropriate padding is not used)

• Deep vein thromboses and pulmonary emboli (these are rare in patients with ALS, but have been encountered with greater frequency in the active treatment arm of some clinical trials)

Diagnosis and treatment

The diagnosis of ALS is primarily clinical. Electrodiagnostic testing contributes to the diagnostic accuracy (see Clinical Presentation and Workup). Making a diagnosis is important to patients and families, allowing them to stop the search for alternative causes of a patient's disability and to focus their attention on treatment.

The Gold Coast criteria provide the minimal requirements for a definitive diagnosis of ALS, and have removed the use of “possible” and “probable” as qualifiers. In a patient presenting with acquired, progressive weakness, ALS may be diagnosed it there are either (1) upper and lower motor findings in one body region or (2) lower motor findings in two regions without an alternative demonstrable cause.

Although ALS is incurable, there are treatments that can extend the length and meaningful quality of life for patients (see Treatment).

Mechanism-specific treatments directed at the processes that cause the disease to evolve after it has expressed itself sufficiently to be diagnosed may, at best, have an ameliorative effect. Treatments that halt the spread of the disease may be more effective than those that try to salvage affected motor neurons. Treatments have emerged in both categories. However, the mainstay of ALS therapy remains  adaptive treatments directed at the clinical manifestations of the disease.

ALS should not be considered a single disease entity, but rather a clinical diagnosis for different pathophysiologic cascades that share the common consequence of causing preferential progressive loss of motor neurons and the orderly dismantling of the motor neuron system.

ALS mechanisms

Previously, research into the mechanisms resulting in sporadic and familial types of ALS had examined several possibilities. For example, excitotoxicity was suggested to occur secondary to overactivation of glutamate receptors.

Oxidative stress linked to free radical formation was also explored as a cause of ALS, owing to the discovery of mutations in the free radical–scavenging enzyme superoxide dismutase 1 (SOD1).[25] Mitochondrial damage was implicated as a possible mechanism as well, as was autoimmunity to calcium ion channels.

The observation of cytoskeletal proteins in cellular inclusions led to consideration of neurofilament defects as another possible cause of ALS. Inclusions in general implicated defects in the proteasome system were considered as a possible unifying mechanism.

More recent research has focused on RNA processing, because several genetic risk factors for ALS are involved in this metabolic pathway, and aggregation of proteins involved in RNA metabolism has been seen in most forms of ALS. Apoptosis has emerged as a possible method of neuronal death, although this is not certain.

Despite such research, no direct mechanism for ALS has been identified. Most investigators and clinicians agree that various factors, possibly a combination of some or all of the above processes, may lead to development of the disease.[26, 27]

If ALS is considered under the umbrella of neuronal system degenerative diseases, then the specificity for the motor system attacked by the disorder can be attributed to a pathologic process that arises within and spreads through the motor neuron system. Similarly, the focal onset (with subsequent spread) can be compared with the pathogenesis of prion disease (focal onset of a misfolded protein and its spread) or malignancy (a single DNA change or summative mutations, with a final one that confers the pathologic activity and its subsequent spread).

Prionlike propagation of misfolding of proteins—in particular, SOD1 and the 43 kDa transactive response DNA binding protein (TDP-43)—has been proposed as a mechanism for the regional spread of ALS symptoms.[25] The accumulation of misfolded proteins has parallels in other neurodegenerative diseases, including Alzheimer, Parkinson, and Huntington disease.

Axonal degeneration

Motor axons die by Wallerian degeneration in ALS, and large motor neurons are affected to a greater extent than smaller ones. This process occurs as a result of the death of the anterior horn cell body, leading to degeneration of the associated motor axon.

As the axon breaks down, surrounding Schwann cells catabolize the axon's myelin sheath and engulf the axon, breaking it into fragments. This forms small ovoid compartments containing axonal debris and surrounding myelin, termed myelin ovoids. Ovoids then are phagocytized by macrophages recruited into the area to clean up debris.

This type of axonal degeneration can be seen in the brain on biopsy as atrophy and pallor of myelinated motor axons in the corticospinal tracts. In cases in which the disease has been active for a long time, atrophy of the primary motor and premotor cortex may be seen as well. On biopsy of the spinal cord, degeneration of the myelinated motor axons with associated atrophy of the anterior motor roots of the spinal cord can be observed.

Wallerian degeneration also occurs peripherally, and collateral branches of surviving axons in the surrounding area can be seen attempting to reinnervate denervated muscle fibers. On muscle biopsy, various stages of atrophy are noted from this pattern of denervation and subsequent reinnervation of muscle fibers.

In typical ALS, certain motor neurons are spared until very late in the disease process. In the brain stem, these include the oculomotor, trochlear, and abducens nerves. In the spinal cord, the posterior columns, spinocerebellar tracts, nucleus of Onuf (which controls bowel and bladder function), and the Clarke column generally are spared, though the Clarke column can be affected in the familial form of the disease.

Pathways to cell death

Pathways that lead to cell death in ALS may be mediated by the following:[28]

• Oxidative damage

• Mitochondrial dysfunction

• Caspase-mediated cell death (apoptosis)

• Defects in axonal transport

• Abnormal growth factor expression

• Glial cell pathology

• Glutamate excitotoxicity

• Aggregation of abnormal proteins

Mutations in the copper/zinc superoxide dismutase 1 (SOD1) gene, which encodes an important antioxidant protein, have been seen in up to 20% of familial ALS patients.[29] Studies in transgenic mice carrying the human SOD1 mutation have provided important information on the pathophysiology of ALS.[28] Also, high levels of oxidative damage to proteins have been found in serum, urine, and cerebrospinal fluid samples from patients, as well as in postmortem samples of patients with both sporadic ALS and SOD1 -familial ALS.[30, 31, 32]

Inferences from animal models, including transgenic models of familial disease, to sporadic human disease are tenuous. However, recognition of the role of glutamate excitotoxicity in sporadic disease and in animal models paved the way to the testing and approval of riluzole, the first treatment that was shown to ameliorate the course of sporadic ALS, extending patients’ lives by 2-3 months.[33, 34]

Derangements of RNA metabolism

The findings below have placed derangements of RNA metabolism at the core of current thinking with regard to the pathophysiology of most types of ALS.

TARDBP gene

In 2006, ubiquitinated inclusions containing pathologic forms of TAR DNA-binding protein-43 (TDP-43) were identified in the cytoplasm of motor neurons of patients with sporadic ALS and in a subset of patients with frontotemporal dementia.[35, 36] TDP-43 is an RNA-processing protein that is normally localized predominantly in the nucleus.

Shortly after their identification in sporadic ALS, TDP-43–positive cytoplasmic inclusions were identified in patients with non-SOD1 familial ALS,[37, 38]  and mutations in the gene on chromosome 1 coding for TDP-43 were identified in patients with sporadic and familial ALS.[39, 40, 41, 42, 43, 44]

Mutations in the TARDBP gene, which codes for TDP-43, account for 5% of patients with familial ALS. In addition, TDP-43 inclusions have been found in more than 90% of patients with sporadic ALS, in patients with Guamanian parkinsonism-dementia complex,[45] in the majority of patients with frontotemporal dementia, and in patients with familial British dementia.[46] A review of the continuum of multisystem TDP-43 proteinopathies concluded that the phenotypic expression is linked to the specific cells that are affected by the proteinopathy.[47]

FUS/TLS gene

In 2009, two groups[48, 49] reported that ALS-6, an autosomal dominant form of ALS, results from mutations in the gene for another RNA-processing protein, fused in sarcoma/translated in liposarcoma, or FUS/TLS. (The gene, FUS/TLS, is located on chromosome 16.) Patients these mutations have cytoplasmic inclusions containing FUS/TLS but not TDP-43. Usually, FUS/TLS, like TDP-43, is concentrated in the nucleus. Mutations in FUS/TLS account for 4% of patients with familial ALS.

Additional evidence

Further support for this idea has come from the following:[50, 51]

• Association and functional studies of another RNA-processing protein, ELP3, in which variants apparently influencing expression alter the risk of ALS

• The observation that other ALS genes, such as ANG, have a second role in RNA metabolism

• The examination of genes implicated in related motor neuron diseases, such as SMN, GARS, and others that cause spinal muscular atrophy, which are also involved in this pathway

In 2011, researchers reported that a large hexanucleotide repeat expansion in the noncoding region adjacent to the C9orf72 gene, which is located on the short arm of chromosome 9, accounts for nearly 50% of familial ALS and frontotemporal dementia (FTD) in the Finnish population and more than a third of familial ALS in other groups of European ancestry.[13, 14]  It is the most common mutation seen in patients with sporadic ALS. One effect of this mutation is the formation of nuclear RNA foci containing antisense RNA repeats. In addition, a novel mechanism of poly-dipeptide production, repeat-associated non-ATG translation (RAN)[52] has been shown to occur in carriers of the hexanucleotide expansion.[53] The abnormal polypeptides form cytoplasmic deposits. It is unclear how these deposits cause disease. In particular, since median age of onset of C9orf72-associated ALS is the same as that of sporadic ALS, and the deposits precede clinical disease by years, it is unclear how the nuclear or cytoplasmic deposits cause ALS or FTD.

Role of TDP-43 in disease propagation

TDP-43 is a nuclear-to-cytoplasmic mRNA transporter protein that misfolds and precipitates in the motor neuronal cytoplasm of patients with sporadic ALS /FTLD and most cases of familial ALS/ FTLD, including but not limited to those inheriting a mutated TDP-43 gene. Abnormal misfolded TDP-43 derived from precipitate of familial (TDP-43 mutant) or sporadic FTLD cases can spread within the motor neuronal  system.[204]

STATHMIN2 – Linking deranged mRNA metabolism and motor neuron degeneration

A link between TDP-43 precipitation and motor neuron degeneration has been identified.[205]

The authors cite: “TDP-43 regulates expression of the neuronal growth-associated factor stathmin-2. Lowered TDP-43 levels, which reduce its binding to sites within the first intron of stathmin-2 pre-messenger RNA, uncover a cryptic polyadenylation site whose utilization produces a truncated, non-functional mRNA. Reduced stathmin-2 expression is found in neurons trans-differentiated from patient fibroblasts expressing an ALS-causing TDP-43 mutation, in motor cortex and spinal motor neurons from patients with sporadic ALS and familial ALS with GGGGCC repeat expansion in the C9orf72 gene, and in induced pluripotent stem cell (iPSC)-derived motor neurons depleted of TDP-43. Remarkably, while reduction in TDP-43 is shown to inhibit axonal regeneration of iPSC-derived motor neurons, rescue of stathmin-2 expression restores axonal regenerative capacity."[205]

These and subsequent findings led to the launch in April 2023 of a phase I clinical trial evaluating the safety and tolerability of QRL-201 in ALS.[206] QRL-201 is an investigational agent designed to restore STATHMIN-2 (STMN2) expression in patients with amyotrophic lateral sclerosis (ALS).

The significance of these developments is that the understanding of the pathophysiology of ALS has moved upstream from the final consequences of the disease, with identification (a) of specific agents of propagation of the disease within the motor system and (b) of a specific protein that when removed results in motor neuronal loss, which can be protected against if its presence if restored. Targeting these pathophysiological mechanisms is more likely to lead to clinically meaningful slowing or possibly halting of disease progression that has been possible with interventions dealing with the end-stage processes impacting death of diseased motor neurons.[207, 208]

Genetic influence on rate of disease progression

One of the most significant aspects of ALS, which varies between individuals thus contributing to the heterogeneity of the disease, is its rate of progression. Several studies have identified genetic conributions to this variability.

Exploring the non-coding genome

The noncoding genome is substantially larger than the protein-coding genome but has been largely unexplored by genetic association studies.[209] A region-based rare variant association analysis of > 25,000 variants in untranslated regions of 6139 ALS whole genomes and the whole genomes of 70,403 non-ALS controls resulted in identification of interleukin-18 receptor accessory protein (IL18RAP) 3' untranslated region (3'UTR) variants as significantly enriched in non-ALS genomes and associated with a fivefold reduced risk of developing ALS.[209]

The finding is of particular significance because it explored genome regions that had not been looked at previously. It remains to be seen, if additional non-coding regions remain to be discovered, and how identification of protective genetic variants can be translated into disease prevention in individuals not carrying those variants.

The role of microRNAs in ALS

MicroRNAs (miRNAs) are short (21-23 nucleotid long), single-stranded, non-coding RNA chains. They regulate the translation of mRNA to protein by binding to complementary RNA segments on mRNA, thereby interfering with mRNA translation. Upregulation of miRNA results in less mRNA translation, down regulation of miRNA results in more mRNA translations. Each miRNA may regulate several hundred mRNAs and each mRNA may be regulated by many miRNAs. MiRNAs determine the identity of specific cells as they differentiate from stem cells. Derangements in miRNA function may result in cellular dedifferention and the emergence of malignancies.[210]

MiRNA dysregulation has been identified in neurodegenerative diseases, as well as ALS. MiRNA profiles have been put forth to serve as biomarkers for the disease, and specific miRNSa have been suggested as linkd to ALS pathogenesis and pathophysiolog, and as therapeutic targets.[211, 212]

Disease onset (pathogenesis)

Making the distinction between the pathogenesis and pathophysiology of ALS matters because the mechanisms underlying each of these stages are probably different. This means that interfering with these mechanisms likely requires different approaches. The interventions to prevent disease onset are probably not the same as those required to slow or halt its progression after onset. Prevention of ALS requires modifying or removing factors that are part of disease pathogenesis. A precondition is identifying probable risk factors for ALS.[54]

In contrast to the approach to understanding the pathophysiology of ALS, which relies on direct biological experiments, the mechanisms that lead to disease onset (ie, pathogenesis) have been inferred from strong circumstantial evidence. In patients with familial ALS, it  is reasonable to assume that the abnormal gene or gene product plays a role in triggering disease onset  and may have a role in disease propagation, but having an abnormal gene is neither necessary nor sufficient for developing ALS.  

Additional factors must be postulated to intervene between birth and disease onset even in patients who develop familial ALS, because the disease does not appear to start at birth, and within a given family there is great variability in the age of onset. Having normal copies of these genes does not prevent development of sporadic ALS.

ALS initiation is a multistep process.[64]  In all likelihood, it takes place in a cortical motor neuron[62] with or without its immediate environment, akin to the initiation of malignancies in dividing cells. The number of steps is 6 in sporadic ALS,[64]  and fewer in carriers of genes for the disease. Different genes require a different number of additional steps for disease initiation.[213] The need for additional steps in patients who are gene carriers explains why they do not have ALS from birth, and why not all carriers develop the disease (“incomplete penetrance.”)

A family history of the disease is obtained in about 5% of patients, and twin studies show a genetic contribution with heritability of about 61%.[10]  More recently, upto 20% of patients presenting with sporadic ALS are found to be carriers of pathogenic or potentially pathogenic genes.[214]

The precise percentage and genes represented depend on the population. In some cases, ALS overlaps clinically, pathologically, and biologically with frontotemporal dementia, and it may share common biologic susceptibility mechanisms with Alzheimer’s disease, Parkinson’s disease, and other neurodegenerative diseases.[11, 12, 13, 14] (See Etiology.)

The multistep hypothesis for disease pathogenesis provides a fairly good idea regarding how and where ALS is initiated. Application of new tools has brought us closer to elucidating the precise cortical pathways involved. A report describes the use of hierarchical clustering on the 5000 most variably expressed autosomal genes identified from post-mortem motor cortex expression data of people with sporadic ALS to indentify networks in which they differed from controls.[215] Three molecular phenotypes were identifed, which reflect the proposed major mechanisms of ALS pathogenesis: synaptic and neuropeptide signalling, excitotoxicity and oxidative stress, and neuroinflammation. Known ALS risk genes were identified among the informative genes of each cluster. Phenotype analysis identified distinct cluster-related outcomes associated with progression, survival and age of death.[215]

The significance of these findings is that (1) they provide genetic underpinnings for the development of sporadic ALS; (2) they localize these underpinnings to the motor cortex; (3) they confirm that the ALS phenotype may be produced through different pathogenic mechansims, with mechanism-related phenotypic variability.

In summary, our current understanding of ALS pathogenesis is sufficiently advanced, that it is time to retire the adage “the cause of ALS is unknown.” It is more correct to say that we have a fairly good understanding of how ALS is initiated and how it spreads, new and more specific information is emerging every year, and that this information has led and is leading to clinical trials focusing more directly on the processes involved early in the course of the disease.

Course of the disease

Loss of motor neurons bridges disease pathophysiology and its clinical expression. When advanced, this loss results in the characteristic picture seen in cross-sections of the spinal cord in ALS. At the level of the muscle, loss of discrete LMNs causes loss of innervation of individual motor units.

Early in the disease, surviving nerve fibers establish connections and reinnervate motor units that have lost their connection to axons that have died; as a result, larger motor units are formed. These large motor units manifest in histologic stains as fiber-type grouping. (See the image below.) They also have special characteristics on electromyographic testing. Later in the disease, when the motor neurons that supply the large motor units die, group atrophy ensues.

Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.

As long as reinnervation can keep up with denervation, clinical weakness may not be detectable, although loss of dexterity may occur. However, as the motor units grow larger and their numbers decrease, the earliest consequence is that affected muscle may fatigue faster than muscle with normal motor units; consequently, one of the first symptoms of ALS may be fatigability of function in the region of onset (for example, “his speech would become muffled toward the end of his sermons”).

As the number of motor units innervating a muscle decreases further, reinnervation can no longer keep up with denervation, permanent weakness develops and progresses, and the affected muscles gradually atrophy. In general, loss of cortical neurons may also result in weakness, but spasticity manifesting as stiffness is a more prominent and disabling UMN symptom.

Risk factors and triggering of onset

Acquired nucleic acid changes may trigger disease onset in sporadic ALS.[55] The past 10 years have seen an increase in evidence supporting this hypothesis. This hypothesis relies on the observation that smoking is the only established risk factor for sporadic ALS[56, 57] and provides a mechanism by which smoking might cause the disease—namely, by induction of changes in nucleic acids. It is supported by clinical observation that age-specific incidence of ALS increases with age. It follows a similar logic that suggests that the alkylating components in the cycad are responsible for delayed onset of Western Pacific ALS/PDC.[58, 59]

Simultaneous initial involvement of cortical and spinal motor neurons responsible for the same body part in ALS and the independent spread of disease at spinal and cortical levels has been shown.[60] These observations have been replicated,[61] although other patterns of spread are sometimes seen. They establish an irrefutable role for corticospinal neurons in the early spread of ALS and provide an observational foundation for postulating the existence of a focus of onset and one or more "agents of spread."[62]

Further support for this hypothesis comes from a statistical examination of acquired somatic mutation rates in humans. Somatic mutations inevitably occur during the many cell divisions required for the single-cell zygote to develop into a full organism; those mutations result in genetic mosaicism, and a small focus of genetically altered cells could be a trigger for ALS.[63]

The increase, with age, of age-specific incidence of sporadic ALS suggests that as time passes there is greater chance for changes to accumulate in nucleic acids that will lead ultimately to the development of ALS. This observation has been recently subjected to confirmatory quantitative analysis.[64] This analysis showed that ALS incidence increases with age in a logarithmic fashion, and the slope of log incidence vs. log age is 5. This suggests a multi-step process, analogous to carcinogenesis,[61] with 6 steps needed for ALS to be triggered.

An alternative trigger for disease onset might be appearance of a misfolded intracellular protein that induces other proteins to misfold, with cell-to-cell transmission of the misfolded protein within the motor network. The difference from classic prion disease is lack of transmissibility by inoculation to other organisms, and the confinement to a neuronal system, or network, with a common function. Hereditary or acquired nucleic acid changes may increase the likelihood that a gene product would be susceptible to misfolding, thus triggering disease onset.

The recent identification of the non-coding C9ORF72 hexanucleotide expansion in many familial and some sporadic ALS cases opens up a possibility that failure of regulation of a normal gene product may underlie ALS initiation and spread.[65, 66, 67, 68, 69, 70] In a broader sense, generation of a faulty regulatory gene product responsible for motor network maintenance, or failure to regulate such a product, may account for the specific disintegration of the motor network. MicroRNAs are particularly attractive candidates for this role.

The affirmation of spread substantiates the concept of a biologic focal onset for ALS. This in turn lends credibility to the concept of a focal trigger for ALS onset that generates the production of 1 or more agents of spread.[55]

Under this hypothesis, disease phenotype in each patient depends on the site of onset and the relative affinity of the specific agent of spread in that patient to motor neurons at the different hierarchical levels of the motor system (prefrontal, corticospinal, spinal/bulbar).[62] The concept of preferential affinity of the agent of spread may apply even to specific motor neurons within a given hierarchy, resulting, for example, in the special phenotypes in which LMNs are predominantly affected (flail arm syndrome, flail leg syndrome).[71]

Most of the biochemical changes found in the upper and lower motor neurons of diseased patients are probably downstream from those that initiate the disease and cause its spread. Some of these changes may represent the processes by which the motor neurons die, but others may reflect the efforts of the motor neurons to survive by compensating for, or “fighting,” the primary pathologic processes driving progression of ALS.

Most amyotrophic lateral sclerosis (ALS) cases are sporadic. We have a fairly good understanding of how sporadic ALS is initiated and how it spreads. New and more specific information is emerging every year (See Disease Onset above). Many abnormal genes have been identified in familial cases and are considered causal, although the precise mechanism by which they cause ALS is unknown for most, with the exception of SOD1 and TDP43.

All of the mutated genes found to give rise to familial ALS have also been found in patients with sporadic ALS. This is to be expected, as the distinction between familial and apparently sporadic disease is based on obtaining a family history, which in turn depends on gene penetrance, family size, age of family members, and the level of knowledge of the person being interviewed.[72]

In addition, first-degree relatives of patients with apparently sporadic disease have an increased risk of ALS. The overall lifetime risk of ALS in these relatives is low, however (approximately 1 in 50).[73]

Familial cases

A family history of ALS is obtained in about 5% of cases and is often consistent with a Mendelian autosomal dominant pattern of inheritance. While most cases of familial ALS are indistinguishable from sporadic disease, others have unique phenotypes.[74]

Juvenile forms of ALS are more commonly familial. Mean age of onset is 10-20 years younger in patients with familial ALS than in patients with apparently sporadic disease, and variability in age of onset between families is greater than variability within families.[18] Age of onset may also be modified by genetic factors independent of the cause of ALS.[75, 76]

Many specific heritable gene mutations have been described in familial ALS (see Table 1, below).[8] A curated, up-to-date list that includes unpublished mutations, genotype-phenotype correlations, and tools for analysis is maintained on the ALSoD website.

Table 1. Familial Forms of ALS ^{[77, 78, 79]} (Open Table in a new window)

About 10-20% of familial ALS cases result from a mutation in the copper/zinc superoxide dismutase 1 (SOD1) gene, also known as ALS1. In general, SOD1 ALS is a LMN form of the disease.[80] The other genes most commonly involved in familial ALS are C9orf72, FUS (ALS6) and TARDBP (ALS10).

SOD1 mutations

More than 140 allelic variations have been seen in SOD1. Some of these variations are characterized by a relatively predictable age of onset or rate of disease progression.

The traditionally used numbering of the amino acids in SOD1, which omits the start codon, is no longer in line with standard practice but will be used here. To translate to the modern numbering, an additional codon should be counted. For example, the D90A mutation frequent in Scandinavia should be p.D91A.

The most common SOD1 mutation in the United States is the A4V mutation, accounting for 50% of SOD1 ALS cases. It causes a rapidly progressive lower motor disease with a mean survival period of 1 year. The North American SOD1 A4V mutation descended from 2 founders (Amerindian and European) 400-500 years ago.[81]

Not all individuals with an SOD1 mutation develop ALS. SOD1 ALS has been shown to be a gain-of-function disease; knockout mice depleted of SOD1 do not develop ALS, and transgenic mice with 1 mutated and 2 normal genes have worse disease than those with 1 normal and 1 mutated gene. Misfolding and precipitation of the abnormal (and normal) SOD1 proteins are considered part of the pathophysiology of SOD1 ALS, and spread of abnormal SOD1 is considered to be the mechanism of spread of disease in mSOD1 patients. How the precipitation of misfolded SOD1 causes the LMN ALS phenotype is still notclear. 

Work in animal models suggests that silencing from birth of the expression of mutant SOD1 by silencing RNA molecules (siRNA) may prevent disease onset in transgenic mouse models.[82] This is an exciting direction for research in humans with SOD1 mutation, but major barriers need to be overcome first, including demonstration that this approach is effective in halting the disease after its clinical onset.[74, 77, 78, 83]  This goal has been attained. A treatment designed to silence mSOD1 after disease onset in humans has shown efficacy albeit limited in slowing disease progression[216] and has been approved by the FDA.[217]

TARDBP and FUS mutations

Gene mutations resulting in abnormalities in proteins that regulate RNA processing have been discovered in patients with autosomal dominant familial ALS. Mutations in the TARDBP gene, which codes for TDP-43, have been found in 5% of patients with familial ALS.[37, 38, 39, 40, 41, 42, 43, 44] Mutations in the FUS gene are found in 3-4% of familial ALS cases.[74]

The mechanism by which these mutations cause ALS is distinct from that which takes place in SOD1 mutations. Although ubiquinated pathologic TDP-43 aggregates have been found in motor neuron cytoplasm of patients with sporadic ALS, they are not specific for this disease and have been found in affected nonmotor cells in patients with Guamanian parkinsonism-dementia complex,[45] British familial dementia,[46] and Alzheimer disease,[84] as well as in most patients with frontotemporal dementia.

Thus, formation of pathologic TDP-43 and its ubiquination may prove to be a mechanism of cell death that is not specific to ALS and is triggered by upstream processes, causing clinical pathology that depends on the cells affected. Conversely, TDP-43 deposition may prove to be a nonspecific defense mechanism involving an unsuccessful attempt to mitigate the action of the true instigators of cell death in a spectrum of neurodegenerative diseases, or it may be an epiphenomenon common to many forms of neurodegenerative diseases. Transgenic animal models with mutated TDP-43 do not develop ALS. However, transfer of misfolded TDP-43 from cell to cell within the motor neuron network is implicated in disease propagation (See Role of TDP-43 in disease propagation, above).

C9orf72 mutation

Studies of families with familial ALS in which some individuals also had frontotemporal dementia found linkage to a region on chromosome 9p21[85, 86, 87] Subsequently, a large genome-wide association study (GWAS) identified single-nucleotide polymorphisms (SNPs) associated with apparently sporadic ALS in the same region. This was confirmed in a further GWAS-wide association study of patients with apparently sporadic ALS and controls from 8 countries,[88] as well as in a Finnish study[89] using family-based samples.

In 2011, two groups reported the discovery of a hexanucleotide (GGGGCC) repeat expansion in the first intron of the chromosome 9 open reading frame 72 (C9orf72) gene­—the function of which is as yet unknown—as the cause of chromosome 9p21–associated ALS and frontotemporal dementia.[65, 66] This expansion of hexanucleotide repeats (from ≤23 in normal individuals to thousands in affected individuals) appears to be the most common genetic abnormality in ALS and in frontotemporal dementia.

The repeat expansion was found in 46.0% of patients with familial ALS, 21.1% with sporadic ALS, and 29.3% with familial frontotemporal dementia, in the Finnish population.[66] In their analysis of an extended North American clinical series, DeJesus-Hernandez et al found the C9orf72 expansion in 23.5% of patients with ALS cases and 11.7% of patients with familial frontotemporal dementia.[65]

More recent reports have found the C9ORF72 repeat expansion in 22-57% of familial ALS patients (depending in part on geographic origin) and in 3.6-7% of sporadic ALS patients.[67, 68, 69, 70] The frequency of the mutation varies widely even within Europe.[90]

Haplotype analysis of 5 European cohorts has shown that the hexanucleotide repeat expansion in C9orf72 had a single founder and arose around 6300 years ago.[90] The haplotype from which the mutation arose is intrinsically unstable, with an increased number of repeats.[90]

The phenotype of C9orf72 -mediated ALS shows distinct pathology, with p62-positive, TDP43-negative inclusions in the cerebellum and hippocampus.[91] Clinically, patients with this mutation have an earlier onset of disease and are more likely to have bulbar-onset disease, cognitive and behavioral impairment, and a family history of frontotemporal dementia than are ALS patients who carry other known mutations.

Other genes in familial ALS

Mutation in the ubiquilin 2 (UBQLN2) gene has been identified as a cause of X-linked dominant familial ALS and ALS with frontotemporal dementia.[92] This finding is of interest because it directly implicates the proteasome pathway in ALS pathogenesis.

Mutation in the profilin 1 (PFN1) gene has been identified in families with familial ALS.[79] The protein encoded by PFN1 plays a critical role in the conversion of monomeric (G)-actin to filamentous (F)-actin. Thus, the identification of this mutation provides further support for the role of the cytoskeleton and axonal transport in ALS pathogenesis.

Sporadic cases

The most widely accepted hypothesis regarding the cause of sporadic ALS posits that interactions between genetic, environmental, and age-dependent risk factors trigger disease onset. (See the image below.) ALS shows complex inheritance, which means that Mendelian, non-Mendelian, and apparently sporadic patterns of inheritance are seen. Smoking is the only environmental risk factor identified to date that may be considered “established.”[56, 57]

The genetic/environmental/age- and time-dependent interactions hypothesis for amyotrophic lateral sclerosis (ALS). Risk factors operate upstream to a putative biochemical transformation (likely an acquired nucleic acid or protein change), which causes the appearance of altered proteins or nucleic acids or abnormal quantities of normal proteins or nucleid acids. These agents spread within the motor system and cause the downstream disintegration of the motor system and the downstream biochemical, histologic, and clinical consequences of ALS. (Adapted from Armon C. What is ALS? In: Amyotrophic Lateral Sclerosis: A Patient Care Guide for Clinicians. Bedlack RS, Mitsumoto H, Eds. Demos Medical Publishing, New York, 2012:1-23)

Several lines of evidence support the hypothesis that genetic risk factors may influence disease initiation in apparently sporadic ALS, apart from finding known Mendelian gene mutations in patients with no family history. Twin studies show a genetic contribution to apparently sporadic ALS, with heritability of 0.61.[10] Increased risk for ALS and (in some studies) clustering of non-ALS neurodegenerative disease is found in relatives of patients with apparently sporadic ALS.[73, 93, 94, 95]

Environmental risk factors

Smoking

Cigarette smoking was the first exogenous risk factor to be considered an established risk factor for ALS[56] (level A conclusion, based on 3 class II studies[96, 97, 98] and 1 class III study[99] ). In addition, a population-based study from the Netherlands demonstrated that current smokers are at increased risk for ALS, with an odds ratio of 1.38, and have shorter survival.[57]

Some aspects of the findings in these studies suggest that smoking may be implicated directly in causing the disease. Overall, studies have shown that active smokers have approximately double the risk of developing ALS compared with never smokers. Former smokers have an intermediate risk.

Identifying smoking as an established risk factor for ALS has the following major implications:

• The findings provide a link between the environment and the occurrence of sporadic ALS; no link had previously been identified with this level of certainty

• Since smoking has no redeeming features, avoidance of smoking may reduce the future occurrence of ALS

• Future studies of risk factors in ALS need to be designed to precisely quantify active and passive smoking, to ensure that other putative risk factors confer a risk that is independent of their association with smoking

• Since some of the mechanisms by which smoking causes other diseases in humans are understood fairly well, recognition of smoking’s role in the occurrence of ALS may help to pinpoint the biologic processes that initiate the disease

Focusing on processes at the initiation of sporadic ALS and close to its initiation, in order to account for its early spread within the motor system, may provide new avenues to treatments to stop its progression. This approach may augment the focus on processes that occur later in the course of the disease and cause the death of motor neurons directly.

The past few years have seen the application of Mendelian randomization methods to assessing risk factors for ALS. Two of the more contentious risk factors considered have been smoking and lipid levels. A 2022 review indicated that several studies conclude that there is a causal link between blood lipids and risk of ALS that has been replicated across different datasets as well as different populations. However, there is doubt that Mendelian randomization studies are useful for other putative risk factors, such as smoking and immune function.[218] These conclusions are subject to limitations acknowledged by the authors, and summarized in part here.

It is difficult to control for survival bias[219] and collider bias[220] in Mendelian randomization studies in ALS. These biases affect how patients and controls get to be included in the samples for Mendelian randomization studies. They affect differently  smoking and cholesterol levels.  Risk factors need to be sought in incidence samples. The samples used for ALS Mendelian randomization samples are prevalence samples. If the risk factor under consideration also affects the patients’ likelihood to be represented in the sample investigated, then finding its presence or absence may be misleading. When sought in prevalence samples, a risk factor may be missed if it is a risk not only for disease onset but also for shortened survival after disease onset, which is the case for smoking. It may be identified spuriously if it confers extended survival after disease onset, which is the case for elevated lipids. Moreover, smoking is a source of mortality competitive to ALS more than elevated lipids, hence may result in underrepresentation of patients in whom ALS has been initiated biologically but not manifested clinically before they succumbed to other smoking-related causes of mortality. Finally – most, if not all, studies considering the role of smoking are biased towards not detecting the effect, as they have not been able to control for the effects of passive smoking in patients and controls.[221]

As further Mendelian randomization studies are pursued in search ot risk factors for ALS – meticulous attention to methods of developing new patient and control samples, with particular emphasis on complete sampling of population-based, incident cases and appropriate controls, may ameliorate some of the limitations inherent in the existing samples. Results of Mendelian randomization studies need to be interpreted in the context of other available information, factoring in also the traditional viewpoints applied to infer causation from association,[222] applied to the 21st century.[223]

Air pollution

Air pollution has been associated with neurodegenerative diseases.[224] It has also been identified as a possible risk factor in ALS.[225, 226, 227]

The role of air pollution is currently being studied through a grant from the CDC to the University of Michigan.[228] Preliminary results reported at scientific meetings have been suggestive.

Military service

Putative risk factors include service in the US military during World War II, the Korean War, and Vietnam,[100] as well as deployment to the Persian Gulf in the 1991 Persian Gulf War.[101] However, close scrutiny has cast doubt on the quality of the evidence supporting the role of these factors in triggering ALS.[101, 102, 103, 104, 105] More recently, a 13-year follow-up study found no excess of ALS among Gulf War veterans.[106]

Repetitive head injuries

A possible increased risk of ALS in Italian professional soccer players was reported in 2005.[110, 111] Initially, it appeared that the apparent increase in risk may have resulted from underestimation of the expected number of cases of ALS.[112, 113, 114, 115, 116] However, a 5-year extension of the follow-up of this cohort showed an unambiguous excess of cases of ALS; 8 cases (including 3 new ones) were reported, even though the number of expected cases was 1.24.[117]

However, the ALS in the professional soccer players displayed atypical features; ie, 5 of the 8 cases had a bulbar onset, and 5 had been diagnosed between 2000 and 2006 (compared with 3 between 1980 and 1999 and none between 1970 and 1979). The authors concluded that the predilection for soccer players to develop ALS derives from a complex interplay between genetic predisposition for physical endurance and external factors such as drugs or herbicides.[117]

A subsequent report suggested that a form of motor neuron disease might develop in individuals, such as boxers, who have sustained repetitive injuries to the brain and developed chronic traumatic encephalopathy (CTE).[118] However, the claim that this was a novel form of motor neuron disease was challenged; instead, the possibility that these cases represented coincidental co-occurrence of ALS was proposed as more plausible.[119, 120, 121]

More recently, a study in retired US National Football League (NFL) players showed that, while their overall mortality was 50% less than expected, their mortality from neurodegenerative diseases was higher than expected. In particular, mortality from ALS and Alzheimer disease was 4-fold higher than expected.[122] These results are based on 7 individuals who died with Alzheimer disease and 7 individuals who died with ALS, out of a cohort of 3439 individuals.

The interpretation of this number as excessive appears to be a consequence of the method used to calculate the expected rate,[112] which may result in underestimation of that rate. In addition, when an apparent excess of neurodegenerative disease appears in the context of greatly reduced overall morality, the emergence of neurodegenerative deaths due to loss of competing causes of mortality needs to be considered.

These reports raised the question whether trauma to the head may be a risk factor for ALS. An evidence-based review of the literature concluded that for instances of isolated head trauma this was not the case.[123]

A subsequently published national population–based case-control study from Sweden found no association of ALS with severe head injury occurring more than 3 years before ALS diagnosis, nor was ALS associated with subtypes of head injury or repeated injuries occurring more than 3 years before diagnosis.[124] Exclusion of injuries occurring within 3 years of diagnosis is necessary to have some assurance that the injury occurred before biologic onset of the disease, which likely precedes clinical onset by several years.[125]

A population-based study from Rochester, Minnesota, showed no increased risk of neurodegenerative diseases among 438 players who played American football in high school between 1946 and 1956, despite poorer protective equipment and less regard for concussions compared with today, and no rules prohibiting head-first tackling.[126]

One report indicated that head injury does not alter disease progression or neuropathological outcomes in patients with ALS.[128]

In conclusion, the association of development of chronic traumatic encephalopathy with multiple instances of trauma to the head is well established, and has been recognized since it was described in boxers as “dementia pugilistica.” The question of if recurrent head trauma also increases the risk of developing ALS, specifically, doubles the risk, remains unresolved.

The balance of the evidence supports the conclusion that head trauma in general is not a risk factor for ALS; and the risk of repetitive head trauma for the general population is uncertain, as the data about risk derive from cohorts of professional athletes.

In the case of the Italian soccer players, their form of ALS was unusual, with most experiencing bulbar onset.

The special circumstances of the NFL players are also of uncertain generalizability, as the data are sparse. One review concluded that professional sports prone to repetitive concussive head and cervical spinal trauma were associated with substantially greater effects compared with (a) nonprofessional sports prone to repetitive concussive head and cervical spinal trauma; (b) professional sports not prone to repetitive head and neck trauma; or (c) nonprofessional sports not prone to repetitive concussive head and cervical spinal trauma.[229]

Risk factors other than the sport itself may be involved, including local environmental risk factors or ingestion of testosterone, anabolic steroids, or other drugs  or supplements.[117, 127]

Other putative exogenous risk factors have not risen to the level of probable. These include exposure to pesticides,[107] postmenopausal hormone use,[54, 108] and physical exercise.[109]

Trauma, physical activity, residence in rural areas and alcohol consumption are probably not risk factors for ALS.[54] Indeed, in the population-based study from the Netherlands noted above, current alcohol consumption was associated with a reduced risk of ALS.[57]

Western Pacific ALS

Most of the research on Western Pacific ALS has focused on Guam. Ingestion of food products derived from the false sago palm, Cycas micronesica (recently separated from Cycas circinalis), was proposed by nutritional anthropologist Marjorie Whiting as the process predisposing to the development of this form of ALS.[129] Despite the cycad nut being subjected to an elaborate preparation process to rid it of toxins before being used as a substrate for flour, some toxic factor was presumed to remain.[130]

In addition, the cycad nut is consumed by the flying fox (a type of bat), which used to be part of the Chamorro peoples' diet on Guam. Toxins from the cycad nut may have been concentrated (bioamplified) in the bat and delivered to the human consumer. The consumption of the flying fox was higher in the mid-20th century than it is now.[131] Most flying foxes consumed in Guam currently are imported.

An epidemiologic study in Guam provided evidence consistent with that hypothesis; its conclusions have been challenged,[131] but the challenges themselves have been questioned.[130]

The nature of the putative toxic component of cycad that may be responsible for delayed-onset neurodegenerative disease has also been a matter of intense debate. One hypothesis is that cycad contains excitotoxic amino acids that do not exert an effect until many years after they have been ingested.[132, 133, 134]

An alternative hypothesis is that alkylating components induce changes in nucleic acids[58, 59] that increase the likelihood that subsequent, additional, age-dependent nucleic acid changes trigger disease onset in Guamanian ALS/Parkinson-dementia complex (ALS/PDC).

Occurrence in the United States

Approximately 5600 people in the United States are diagnosed with ALS each year. The annual incidence is 2-3 per 100,000 population; this is about equal to that of multiple sclerosis and 5 times higher than that of Huntington disease. It is estimated that as many as 18,000 Americans may have ALS at any given time.

The lifetime risk for developing ALS for individuals aged 18 years has been estimated to be 1 in 350 for men and 1 in 420 for women.[112] These estimates are close to those reported from 4 European registries, using different methods.[135, 136, 137]

International occurrence

Age-adjusted European incidence data are similar to those for members of the US population who are of European descent.[135, 138] Most variability between countries has been attributed to different age composition or differences in case finding. More recent data, however, suggest that ethnic variability in disease incidence exists[139, 140] that may not be explained entirely by differences in case finding, with lower incidence in nonwhites or individuals of mixed ethnicity. Although this possibility is not supported by all studies, it merits further examination.[141]

Finland has one of the highest rates of ALS in the world; the disease occurs in the Finnish population nearly twice as frequently as it does in other populations of European ancestry.[89] A study from Finland found 2 clusters of cases based on geographic location at time of death and a cluster based on time of birth that closely matched one of the time-of-death clusters.[142] It was recognized that these results could be consistent with either a genetic or environmental cause. With the discovery of the hexanucleotide repeat expansion in C9orf72, most cases of ALS in Finland have been confirmed to be due to genetic factors.

Race-related demographics

In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.[139] Uncertainty surrounds this finding, however, as it has been considered to be an artifact of reduced case-finding in nonwhites. This reservation may be less relevant today due to increased awareness of ALS in all communities, greater availability of health insurance coverage nationwide, and more widespread presence of ALS centers providing care regardless of the patient’s insurance status. Evidence for racial differences has come from an epidemiologic study in Cuba[140]  where access to care is considered uniform.

Small population clusters have been identified that have higher rates of ALS. The Chamorro people of Guam and Marianas Island, residents of the Kii peninsula of Japan’s Honshu Island, and the Auyu and Jakai people of southwest New Guinea have a higher incidence of ALS than is found in populations elsewhere in the world.[8] The Chamorro population in Guam in the mid-20th century had an annual incidence of ALS (often in association with parkinsonism and dementia) as high as 70 cases per 100,000 (see Pathophysiology).[132] The incidence has since decreased to 7 cases per 100,000. These findings may be due to environmental exposure rather than to race.

Sex- and age-related demographics

For most of the lifespan, the incidence of ALS is higher in men than in women, with an overall male-to-female ratio of 1.5-2:1.[18] Later in life, the incidence tends to equalize; this occurs at age 40-50 years in some populations and after the age of 65-70 years in others.[143]

Onset of ALS may occur from the teenage years to the late 80s; the incidence rises with increasing age until approximately age 75-80 years. Mean age of onset of sporadic ALS is 65 years; mean age of onset of familial ALS ranges from 46-55 years.

ALS is a fatal disease. Median survival is 3 years from clinical onset of weakness. However, longer survival is not rare. About 15% of patients with ALS live 5 years after diagnosis, and about 5% survive for more than 10 years. Long-term survival is associated with a younger age at onset, being male, and limb (rather than bulbar) symptom onset. Rare reports of spontaneous remission exist.[144] In familial ALS that results from an alanine-to-valine mutation in codon 4 of the SOD1 gene (A4V mutation), average survival is 12 months from disease onset.81 Survival in other SOD1 mutations is greater than in sporadic ALS.[230]

Regionally limited forms of motor neuron disease (ie, brachial biplegia, lumbosacral biplegia, and progressive bulbar palsy [PBP] that remains restricted[145] ) progress slower than does classic ALS. Progressive muscular atrophy (PMA), distinct from classic ALS because of lack of upper motor neuron (UMN) findings, progresses at the same rate as classic ALS. UMN-predominant ALS progresses at a slower rate. These observations suggest that it is the loss of LMNs that determines the prognosis. Survival in cases of primary lateral sclerosis (PLS), which is, strictly speaking, not a form of ALS, is measured in decades.

Frontotemporal executive dysfunction may precede or follow the onset of ALS, but most patients with ALS do not have overt dementia, and cognitive impairment is usually subtle.[146] Approximately 15% of patients with ALS meet criteria for frontotemporal dementia (FTD). Patients with ALS associated with FTD have shorter survival than do those with ALS alone.[147, 148]

A readily available predictor of survival is the rate of observed disease progression. This may be estimated in more than one way. First is the time between symptom onset and diagnosis. Shorter time translates into worse prognosis. Second is the degree of loss of function at the time the patient is first seen, using quantitaitve measures such as the ALS Functional Rating Scale (ALSFRS).[149]  However, not all losses on the ALSFRS-R are of equal prognostic significance: bulbar losses result in a worse prognosis than spinal losses of equal numerical value. Third, true estimates of rates of progression may be derived as a ratio between loss and time since symptom onset. The measurement of functional loss may be obtained using the ALSFRS-Revised (ALSFRS-R), the forced vital capacity (FVC) as percent of predicted, strength, or motor unit number estimates (MUNEs).[150, 151, 152, 153, 154]  In each case, the current number is subtracted from a presumptive baseline to give the magnitude of the loss.

Multifactorial algorithms to predict survival and loss of critical functions have been developed.[231, 232, 233, 234]

In the 2021 meta-analysis by Su et al,[234] NFL (HR:3.70, 6.80, in serum and CSF, respectively), FTD (HR:2.98), ALSFRS-R change (HR:2.37), respiratory subtype (HR:2.20), executive dysfunction (HR:2.10), and age of onset (HR:1.03) were superior predictors for poor prognosis, but pLMN or pUMN (HR:0.32), baseline ALSFRS-R score (HR:0.95), duration (HR:0.96), and diagnostic delay (HR:0.97) were superior predictors for a good prognosis.

This meta-analysis also highlights the emergence of biomarkers as predictors of prognosis. Of these, Neurofilament Light (NFL) has been the most reliable at reflecting rate of progression, with higher levels reflecting faster progression. Use of biomarkers has not yet entered routine clinical practice but is becoming more frequent in the research setting to stratify patients based on a biological measure of disease progression.

Some prognostic algorithms are available as online tools, intended for use by physicians, recognizing that receiving stark unfavorable information online can be disturbing for patients.

A final consideration is what degree of prognostic precision is relevant to patients, and whether complex algorithms confer added precision that is meaningful to patients, beyond what may be inferred more intuitively by ascertaining their age, rate of progression and degrees of bulbar, respiratory and cognitive involvement at presentation.

Measures of disease progression

Roche et al proposed a system of stages (the King's staging system), the timing of which is standardized as proportions of elapsed time through the course of ALS.[155] The milestones, and their typical time of occurrence, are as follows:

• Stage 1: Symptom onset (involvement of first region)

• Stage 2A: Diagnosis (35% of the way through the disease course)

• Stage 2B: Involvement of second region (38%)

• Stage 3: Involvement of third region (61%)

• Stage 4A: Need for gastrostomy (77%)

• Stage 4B: Need for noninvasive ventilation (80%)

• Stage 5: Death

It may be seen that most patients are diagnosed at a point at which ALS has extended to involve at least 2 regions and that the needs for gastrostomy and noninvasive ventilation (NIV) are usually recognized almost at the same time. These percentages are consistent with the numbers usually cited of 12 months’ mean time from onset to diagnosis and 3 years’ mean duration of disease from onset to death.

A standard operating procedure has been designed to help apply this staging system.[235]

An additional staging system, the Milano–Torino (MiToS) Staging system, has also been developed. It comprises six stages based on functional impairment as assessed by the revised ALS Functional Rating Scale (ALSFRS-R).[236]

The systems are complementary, with the King’s system predicated on anatomical progression and the MiTos system on functional decline. The King’s clinical staging has a higher resolution in early-mid diseases stages and the MiToS system in late disease stages.[235, 237, 238]

The need for these staging systems has arisen, in part, in order to permit demonstrating efficacy of treatments by showing by how many months they delay transition from one stage to another, thereby providing clinically meaningful measures of slowing disease progression, beyond what may be understood by percentage of slowing of a slope.

Discussing prognosis with the patient

Patients the author has surveyed have indicated ambivalence about being offered individualized information early in the course of the disease (when it may matter most).[157] The author does not offer patients individualized prognostic information at the first visit. When patients do request it, he asks them to consider the possible implications of the answers they may receive and to ask him again at a subsequent visit. It is also helpful to discuss the implications of the rate of disease progression, based on the joint observations of the patient and the physician.

The following education resources are available to patients with ALS:

• ALS Association, Living With ALS Manuals

• Muscular Dystrophy Association: MDA ALS Caregiver’s Guide

• ALS 1996 and Beyond: New Hopes and Challenges. A Manual for Patients, Families and Friends (Fourth edition, 2007)[158]

• ALS newsletter of the Muscular Dystrophy Association

Informational web sites include the following:

• Muscular Dystrophy Association

• ALS Association of America

• National Institute of Neurological Disorders and Stroke (NINDS)

• Motor Neurone Disease Association (England, Wales, and Northern Ireland)

For patient education information, see the Brain and Nervous System Center, as well as Amyotrophic Lateral Sclerosis (ALS, Lou Gehrig’s Disease) and Advance Directives.

The diagnosis of amyotrophic lateral sclerosis (ALS) is primarily clinical. When the disease has progressed far in its course and involves many parts of the body, the patient’s appearance and the findings on the neurologic examination may provide sufficient evidence for the diagnosis. When a patient presents with the first symptoms, however, making the diagnosis is not straightforward.[19]

ALS may be suspected whenever an individual develops insidious loss of function or gradual, slowly progressive, painless weakness in 1 or more regions of the body, without changes in the ability to feel, and no other cause is immediately evident.

In lower motor neuron (LMN) involvement, fasciculations may occur early on in the disease, particularly in the tongue and limbs. Patients with upper motor neuron (UMN) involvement generally are hyperreflexic and stiff. Reflexes may be diminished due to LMN involvement. UMN symptoms may include spasms and sudden, uncontrolled straightening movements of the lower limbs.

In 75–80% of patients, symptoms begin with limb involvement, while 20–25% of patients present with bulbar symptoms. For those with limb involvement at presentation, the frequency of upper limb versus lower limb involvement is approximately equal.

Patients with upper limb onset have twice the likelihood for onset in the dominant arm, compared with the nondominant arm. There is equal likelihood for presentation in either lower extremity. Women have a greater frequency of bulbar (speech dysfunction) onset than men. These observations suggest a greater likelihood for network dismantling to start where there is a better-developed, or more complex, cortical network.

Patients who have lower limb onset initially may complain of tripping, stumbling, or awkwardness when running. Foot drop is common, and patients may report a "slapping" gait.

Persons with upper limb onset may experience reduced finger dexterity, cramping, stiffness, and weakness or wasting of intrinsic hand muscles. This may lead to difficulty with actions such as buttoning clothes, picking up small objects, or turning a key. These patients may develop wrist drop.

As ALS progresses, muscle atrophy becomes more apparent, and spasticity may compromise gait and manual dexterity. Immobility, if coupled with spasticity, may lead to the development of painful joint contractures. Muscle cramps are common. In some patients, persistent stiffness or cramping of muscles may stress the related joints and the back. This can usually be ameliorated with medications and physical therapy exercises to relax the muscles and maintain joint range of motion.

Bulbar involvement

A mixture of spastic and flaccid components may characterize speech, resulting in a dysarthria with severe disintegration and slowness of articulation. Hypernasality occurs from palatal weakness, and patients may develop a strained, strangled vocal quality. With time, speech may be lost, and patients may become dependent on other forms of communication, such as writing, communication boards, or speech-generation devices.

Patients with bulbar involvement may develop swallowing difficulties (dysphagia). Swallowing liquids requires the greatest oropharyngeal muscle control; therefore, patients usually report more difficulty with liquids than with solids. Aspiration or choking during a meal may occur.

Drooling affects some patients and results from a combination of excessive salivation, poor swallowing, and poor lip control. The problem can usually be ameliorated effectively with oral medications or a scopolamine patch, but other methods, such as salivary gland irradiation or injection of botulinum toxin, are sometimes required.

Pseudobulbar symptoms

These consist of exaggerated, involuntary emotional responses. The response may be of one type (laughter or crying) or, less commonly, alterations in emotive expressions. Episodes of intense laughter may be followed immediately by tears. The patient's response often does not correspond to an apparent social stimulus or the current psychosocial situation; it may instead be an exaggerated response to a minor trigger. The patient is aware of the lack of control. Symptoms can often be ameliorated by medications.

Preserved functions

Certain motor neurons usually are spared in ALS, which means that some functions are preserved. Most patients retain extraocular movements and bowel and bladder control. With progressive disease, patients may develop problems with urge incontinence and constipation because of weak abdominal musculature, but sphincter control generally is unaffected.

Since the disease primarily involves motor neurons, sensory function typically is preserved, although a minority of patients complains of some numbness and paresthesias. Abnormalities have been reported on sensory nerve conduction studies in a small number of patients with ALS,[159] but these findings often reflect the presence of an unrelated, coexistent condition.

Skin integrity in ALS usually is maintained, primarily due to the combination of preserved sensory function and continued control of bowel and bladder function. Some studies of patients with ALS have found morphologic changes in the skin that are complex and poorly understood but that may contribute to preservation of skin integrity.

Family history

Obtaining a thorough family history is pertinent in the examination of all patients. Patients with a family history of Mendelian ALS may be considered to have definite ALS as soon as any evidence of motor neuron disease arises that cannot be accounted for by an alternative explanation, regardless of the extent of involvement. Some experts, however, require that the abnormal gene be demonstrated in the patient. Genetic testing is typically recommended when a mode of inheritance, most often autosomal dominant, is recognized, but the gene has not yet been identified in the family.

A family history of ALS in a second- or third-degree relative or any family history of frontotemporal dementia should also be regarded as evidence in support of a diagnosis of familial ALS.[160, 161]

The symptoms that some patients with ALS may experience and the signs that are found on their neurologic examination are summarized below. Not all patients experience all symptoms or have all signs.

Motor neuron manifestations

Findings reflecting upper or lower motor neuron dysfunction include the following:

• Weakness (classic ALS weakness, however, is usually from LMN dysfunction or loss)

• Difficulties with speech and swallowing

• Unsteadiness

Findings reflecting UMN dysfunction include the following:

• Stiffness (spasticity)

• Tendon reflexes that are brisk or that spread abnormally (hyperreflexia)

• Presence of abnormal reflexes (eg, Babinski, Chaddock, or Hoffman signs)

• Loss of dexterity in the presence of normal strength

• Muscle spasms

Findings reflecting LMN dysfunction include the following:

• Twitching muscles (fasciculations)[162]

• Muscle cramps

• Reduction of muscle bulk (atrophy)

• Foot drop

• Depressed reflexes

• Breathing difficulties

The key finding in an involved limb is a combination of upper and lower motor neuron dysfunction, as when a weak, atrophic, fasciculating muscle also has increased tone and hyperreflexia.

Emotional and cognitive symptoms

While the symptoms of motor dysfunction in ALS are best recognized, affecting all patients with the disease, a fair proportion of patients also experience emotional and special cognitive difficulties. Emotional manifestations of ALS include involuntary laughing or crying and/or depression. Cognitive difficulties involve executive function impairment and/or behavioral changes.

Frontotemporal executive dysfunction may precede or follow the onset of ALS, but most patients with ALS do not have overt dementia, and cognitive impairment is usually subtle.[146] Approximately 15% of patients with ALS meet the criteria for frontotemporal dementia (FTD).[147, 148]  An additional 30-40% may have cognitive impairment detectable by special testing. FTD interferes with patients' acceptance of supportive treatment recommendations and makes them harder to manage. On the average, ALS patients who have FTD live 12 months less than comparable patients without FTD.[163]

Bulbar symptoms

Bulbar symptoms manifesting as dysarthria or dysphagia are the most common ALS presentation next to limb involvement, affecting 20-25% of patients. Rarely, patients with ALS may present with respiratory muscle weakness, generalized weakness, or difficulty with head control. Those with respiratory muscle weakness may develop disturbed nocturnal sleep and exhibit excessive daytime sleepiness.

Truncal difficulties

Patients with axial truncal weakness have difficulty maintaining an erect posture when standing; to assist in attaining a standing position, they may support their torso by “walking” their hands up their thighs. Some patients feel more secure when pushing a heavy object on wheels, such as a grocery cart.

Gold Coast criteria

These criteria have simplified the diagnostic process.[199] ALS may be diagnosed in a patient with acquired, progressive weakness by showing either (a) UMN+LMN findings in one limb or (b) LMN findings in two limbs, and excluding alternative causes with appropriate history, imaging and laboratory studies.

El Escorial (World Federation of Neurology) criteria

These criteria are in widespread use, particularly to characterize patients entering clinical trials. According to criteria from the El Escorial World Federation of Neurology, the diagnosis of ALS requires the presence of the following:[164]

1. Signs of lower motor neuron (LMN) degeneration by clinical, electrophysiological or neuropathologic examination,
2. Signs of upper motor neuron (UMN) degeneration by clinical examination, and
3. Progressive spread of signs within a region or to other regions, together with the absence of:
   • Electrophysiological evidence of other disease processes that might explain the signs of LMN and/or UMN degenerations; and
   • Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiological signs.

The individual findings in extremity and bulbar muscles are combined in an algorithm that expresses in each patient the extent of disease involvement at the time of the examination.

The WFN (ElEscorial) criteria use adjectives that in usual speech reflect the degree of certainty. However, when these adjectives are applied in the context of diagnosing patients with ALS, they need to be understood as reflective of the degree of clinical involvement rather than the degree of certainty in the diagnosis, particularly if no alternative diagnosis has been found and the disease has progressed beyond a single limb. This distinction can be confusing for patients.

The WFN criteria recognize the following 4 regions, or levels, of the body (see the image below):

• Bulbar: Muscles of the face, mouth, and throat

• Cervical: Muscles of the back of the head and the neck, shoulders, upper back, and upper extremities

• Thoracic: Muscles of the chest and abdomen and the middle portion of the spinal muscles

• Lumbosacral: Muscles of the lower back, groin, and lower extremities

Although the names of these regions appear to describe neurologic segments, the terms actually refer to functional regions of the body. For example, the small muscles of the hands are innervated by thoracic motor neurons but are counted in the cervical region.

The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities).

The WFN categories are as follows:

• Clinically definite ALS: UMN and LMN signs in at least 3 body segments

• Clinically probable ALS: UMN and LMN signs in at least 2 body segments with some UMN signs in a segment above the LMN signs

• Clinically probable, laboratory-supported ALS: UMN and LMN signs in 1 segment or UMN signs in 1 region coupled with LMN signs by electromyography (EMG) in at least 2 limbs

• Clinically possible ALS: UMN and LMN signs in 1 body segment, UMN signs alone in at least 2 segments, or LMN signs in segments above UMN signs

• Clinically suspected ALS (carried forward from the original El Escorial criteria): Pure LMN syndrome with other causes of LMN disease adequately excluded

Qualifiers

Originally, it was thought that the degree of certainty of diagnosis was increased by the number of body segments that demonstrated UMN and LMN signs; hence, the choice of qualifying adjectives. The criteria were designed to be usable even if no adjunctive testing was available, in which case the qualifiers did have implications in their literal sense.

However, the qualifiers have effectively lost their meaning, in terms of making the diagnosis, as a result of the following:

• The current ability to exclude alternative causes for progressive motor weakness

• The demonstration that patients with possible ALS and no alternative explanation for their condition have progressive disease

• The demonstration that patients with pure LMN symptoms of the progressive motor atrophy (PMA) variety have a course no different than that of classic ALS

The qualifiers continue to reflect the extent of involvement at time of diagnosis or subsequent evaluation. Recruitment to clinical trials previously was limited to patients with definite or probable ALS (including probable, laboratory-supported ALS), but more recent clinical trials have included patients with “possible” ALS. Their progression has been affirmed explicitly.

Patients with progressive bulbar palsy (PBP) may be classified, while the disease is restricted to the bulbar region, as having “suspected ALS” if only UMN or LMN abnormalities are evident, and as “possible ALS” if there is UMN and LMN involvement. When neurophysiologic or clinical spread beyond the bulbar level is evident, the condition would be reclassified as probable; laboratory-supported, probable; or definite ALS.

The term “suspected ALS” has special meaning in the WFN classification system because it is applied to patients with a pure UMN presentation, particularly if they cannot yet be diagnosed with primary lateral sclerosis, and to patients with a pure LMN presentation (particularly early in their presentation) before enough time has elapsed to be sure that their condition will remain restricted to LMNs and might therefore be more precisely described as PMA.

This has a practical implication, because patients with primary lateral sclerosis have a course that is measured in decades (approximately 20 y). Some patients with a predominantly UMN form of ALS may also have a longer course than those with classic ALS.

Since the distinction between a diagnosis of PMA and one of laboratory-supported probable ALS hinges on the identification of 1 UMN sign at some point in the patient’s disease, this distinction may be primarily of significance to researchers. For clinicians and patients, rate of progression is likely to be of greater concern, as it is the factor that determines the patients’ course and outcome.

In day-to-day practice, clinicians will inevitably use the term suspected ALS whenever they believe ALS to be a possibility, regardless of the extent of clinical involvement at the time, and may or may not use the WFN qualifiers when they conclude that the patient has ALS. This leads to clearer terminology in practice; the patient is either suspected of having ALS or confirmed as having the disease, or a different diagnosis is made.

Awaji criteria

Since the introduction of the revised El Escorial criteria, attempts have been made to permit earlier diagnosis of ALS. Additional approaches have been proposed for the analysis of clinical and electrophysiological data in order to facilitate earlier diagnosis of probable ALS.[165]

The Awaji criteria consider equally the clinical and neurophysiological evidence of LMN involvement.[166]  Acute and chronic signs of denervation should also be taken as equivalent, with only one type of change necessary to imply limb involvement. In parallel, it has become evident that most patients with possible ALS who have progressive disease with lower motor neuron findings and in whom other causes of focal disease have been excluded are destined to progress and manifest the full spectrum of the disease, so that they may be considered to have ALS, including for the purpose of enrollment into clinical trials. Finally, patients characterized as having clinically suspected ALS, due to absence of upper motor neuron findings, also named PMA (progressive muscular atrophy), have clinical courses that are usually indistinguishable from those of patients with ALS. The exceptions are patients with specific syndromes (e.g., brachial biplegia, lumbosacral biplegia) who tend to have a slower course, and some patients with particularly slow or fast forms of lower motor neuron disease.

In addition, efforts have been made to introduce biological and radiological markers to assist in diagnosing ALS. However, most of the work evaluating these markers has been done in patients in whom the diagnosis was not in question. It is impossible to say if these markers would help make the diagnosis of ALS in individuals who do not meet clinical and electrophysiological criteria for the disease.

In summary, earlier diagnosis of ALS is possible today in individual cases, relative to years past, if alternative causes for early, limited, progressive disease are excluded. The requirements to exclude alternate diagnoses and observe progression are more stringent in very early disease. However, in aggregate reported data of ALS clinic patients and of patients enrolled into clinical trials the average time from clinical disease onset to diagnosis has remained unchanged, and continues to hover around 12 months.  

Amyotrophic lateral sclerosis (ALS) may not lend itself to a quick definitive diagnosis early in its presentation. Often, neurologists need many months to exclude all other possible diagnoses in a patient presenting with upper and lower motor neuron signs. In some cases the diagnosis is fairly obvious even in its early stages.

Nerve conduction studies and needle electromyography (EMG) are useful for confirming the diagnosis of ALS and for excluding peripheral conditions that resemble ALS.

Laboratory tests are performed primarily to rule out other disease processes; results generally are normal in ALS.

Biochemical markers in blood are used almost routinely to identify diseases that could mimic ALS. Examination of cerebrospinal fluid usually is not necessary unless the patient has a pure upper motor neuron (UMN) or pure lower motor neuron (LMN) presentation, in which case it can be helpful in excluding inflammatory conditions, neoplastic infiltrations, or infections.

Genetic testing

Genetic testing may be performed to identify genetic defects in some familial types of ALS, as well as other inherited motor neuron diseases. In the future, genetic testing may become more routine, given recent research showing that in some populations the C9orf72 mutation is present in a high proportion of patients with no family history of ALS.

The role of genetic testing in patients with sporadic disease has been debated among ALS experts.[167] Patients with sporadic disease who are considering genetic testing should take the time, through genetic counseling, to study the implications for themselves and for their first-degree relatives, Ideally, the first-degree relatives should be involved in the counseling process as the results of genetic testing impact them more than they impact the patient. In some centers, genetic testing is routine for all patients with ALS. It has been advocated as necessary for all patients entering clinical trials, as treatment responses may vary based on patients’ genetic profiles. A current instance under evaluation is the effectiveness of lithium in patients with ALS. After initial enthusiasm, it was shown to be ineffective in several large placebo-controlled studies.[239, 240, 241]

It then appeared, in a post-hoc analysis, that there may be a subgroup of patients, those who are homozygous for the C-allele at SNP rs12608932 in UNC13A, in whom lithium might be effective. A clinical trial has been registered to explore this possibility.[242]

Imaging

Imaging studies need to be tailored to the patient’s clinical presentation. Neuroimaging may include computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the brain and spinal cord.

Muscle or nerve biopsy

Muscle biopsy is needed only rarely but may be considered if the presentation of ALS is atypical. The results will confirm the presence of signs of denervation and reinnervation or may lead to an alternative diagnosis, such as inclusion body myositis.

The presence of small, angular fibers is consistent with neurogenic atrophy (denervation). Fiber-type grouping is consistent with reinnervation.

It is common to examine at least 3 levels—cervical/thoracic/lumbar paraspinal muscles—and bulbar muscles, as follows:

• Most involved limb first: Two or more weak muscles with different innervation

• Distal muscles of other possibly abnormal extremities

• If other levels are not abnormal, then check bulbar muscles

EMG may show fibrillation and fasciculation potentials. The motor units may be polyphasic and have high amplitude and long duration.

Motor unit recruitment

The pattern of recruitment of motor units may be abnormal due to loss of anterior horn cells and a reduction in the number of viable motor axons to activate the muscle(s) involved. This loss results in increased firing frequency of surviving motor units, because fewer anterior horn cells (motor axons) are available to be activated as the amount of effort increases.

Muscle innervation

Recently reinnervated muscles demonstrate variability of morphology on needle EMG examination. This is because of sprouting nerve terminals that are unmyelinated, have slower conduction, and may cause intermittent conduction block. Increased polyphasia of voluntary motor unit action potentials is a result of asynchronous firing of reinnervated, unmyelinated muscle fibers resulting from slowed terminal nerve conduction.

Over time, the voluntary motor unit action potentials increase in size and duration because of collateral sprouting, bringing more muscle fibers into the motor unit. With maturation of the terminal sprouting, voluntary motor unit action potentials increase in size in reinnervated muscle fibers, restoring their size and a greater degree of motor firing synchrony due to myelinization of terminal nerve fibers and more rapid terminal nerve conduction.’

Denervation

Signs of active and chronic denervation are likely to be observed. Fibrillation potentials and positive sharp waves represent active denervation. Chronic denervation is demonstrated by evidence of large motor unit potentials with increased duration and amplitude, as well as polyphasic potentials, reduced recruitment, a reduced interference pattern with firing rates higher than 10 Hz, and unstable motor unit potentials.

Multispike and fasciculation potentials

Complex, repetitive discharges occur in ALS of long duration, as they do in other chronic neurogenic atrophic conditions. These are regularly discharging multispike potentials that are time-locked. Other than an EMG finding associated with a chronic neurogenic atrophic condition, this finding has no other unique significance.

Fasciculation potentials are seen frequently but not invariably in ALS. Their presence is not specific to ALS; they may occur in other conditions, some completely benign.

Conduction studies

Motor and sensory nerve conduction studies are performed primarily to rule out other disorders. In patients with predominantly LMN findings, the presence of conduction block may point to treatable diseases such as multifocal motor neuropathy or motor chronic inflammatory demyelinating polyneuropathy.

Sensory nerve conduction studies are usually normal. Less than 10% of patients with ALS have abnormal sural sensory nerve conduction studies. Patients over age 60 years commonly lose the sural sensory nerve action potential (SNAP), but this is attributable to normal aging.

In late stages of ALS, LMN involvement may be extensive; in such cases, compound muscle action potentials may be reduced. Hallmark findings in the electrodiagnosis of ALS are normal sensory nerve conduction studies and abnormal motor nerve conduction studies, with reduced motor compound muscle action potentials.

Neuromuscular transmission instability of collateral nerve terminal sprouts in ALS patients presents as a decrement with slow repetitive stimulation. This instability is present in less than 50% of patients with ALS. The decrement in ALS is usually less than 10%. In contrast, compound muscle action potential decrements greater than 20% on repetitive stimulation of motor nerves are seen in myasthenia gravis. In ALS, this is usually a late finding, whereas in myasthenia gravis, this is an early finding.

Electrophysiologic features compatible with UMN involvement include an increase of up to 30% in central motor conduction time determined by cortical magnetic stimulation. However, central electrophysiologic studies are currently not part of the routine evaluation of patients with ALS, because whether emergence of central studies abnormalities precedes that of clinical signs of UMN involvement has not been determined.

Low or irregular firing rates of a few voluntary motor unit action potentials on maximal effort may be seen during routine needle examination of UMNs. However, this feature is nonspecific. It may be seen in other settings if patients have difficulty activating specific muscles because of UMN disease, pain inhibition, or poor cooperation.

Motor unit number estimate

The motor unit number estimate (MUNE) is a nerve conduction study technique that can quantify the numbers of motor units innervating an individual muscle.[168] It may be used to help with the diagnostic process in rare cases in which clinical or electrodiagnostic LMN involvement otherwise cannot be shown. For example, MUNE showing numbers below the lower limit of normal in distal upper and lower extremity muscles establishes the diagnosis as ALS.

MUNE may be used to separate patients into faster and slower ALS progression groups.[169] However, other measures of disease progression that are easier to obtain, such as those derived using the ALS Functional Rating Scale-Revised (ALSFRS-R), may serve this purpose. Also, patients the author has surveyed have reflected ambivalence or reluctance at the prospect of receiving prognostic information early in the course of the disease, which is when such information is of greatest relevance.[157]

MUNE is appealing as a quantifiable, physiologic measure of disease progression that is independent of patient effort and is a measure of pure LMN involvement. Nevertheless, the error inherent in the estimation process precludes its use as the primary measure of efficacy of putative, mechanism-specific interventions to slow disease progression.

Characteristics of other neuropathies

Multifocal motor mononeuropathy

Other disease processes may be suggested by their characteristic electrophysiologic presentation. Multifocal motor mononeuropathy may be suggested by the following:

• Motor conduction block in multiple nerves

• Motor conduction velocities less than 70% of the lower limit of normal, and distal motor latencies greater than 30% of the upper limit of normal values

Chronic inflammatory demyelinating polyradiculoneuropathy

This condition may be suggested by the features listed above, together with the following:

• Low sensory nerve action potential amplitudes with slow conduction if not attributable to entrapment syndromes or known concomitant pathology, such as diabetes

• F-wave or H-wave latencies greater than 30% above established normal values

Sensorimotor peripheral neuropathy

A generalized axonal sensorimotor peripheral neuropathy may be suggested if motor and sensory fibers appear affected equally without excessive slowing or if sensory fibers are affected more than motor fibers. However, it must be recognized that mild sensory abnormalities may be found occasionally in patients with ALS without sensory symptoms and that the lower limits of normal in persons aged 60 years or older are lower than those for younger individuals.

Inclusion body myositis

Inclusion body myositis may be suggested by a characteristic pattern of distribution of affected muscles and by a mixed pattern of large and small motor unit potentials on needle examination. Other myopathies may also be suggested if small, rapidly firing motor unit potentials are found, rather than those characteristic of a neurogenic process.

Primary lateral sclerosis and monomelic amyotrophy

Primary lateral sclerosis may be suggested if LMN involvement is minimal or absent, particularly if that remains the case 3 years (or more conservatively, 5 years) after clinical onset of disease. Monomelic amyotrophy may be suggested if no evidence of disease is found outside 1 limb several years after its onset.

Laboratory tests sometimes ordered in the evaluation of a patient with possible ALS include anti-ganglioside M1 (anti-GM1) antibodies, as these can be seen in patients with multifocal motor neuropathy with conduction block. Vitamin B12 and folate levels, HIV status, Lyme serology, and creatine phosphokinase (CPK) determinations may also be performed when indicated by clinical circumstances. The CPK level may be elevated in ALS, but this is not a diagnostic finding.

The following tests may also be considered:

• Serum protein electrophoresis and immunoelectrophoresis

• Syphilis tests

• Thyroid function tests

• Parathyroid hormone assay

• Vitamin B1 assay

• Genetic testing (especially in familial cases)

If myasthenia gravis is under consideration, antiacetylcholine receptor antibody and anti-muscle specific kinase (MuSK) antibody assays should be ordered.

Urinary 24-hour collections for heavy metals may be requested if there is reason to suspect recent exposure. Hexosaminidase A in urine may be checked when adult Tay-Sachs is suspected strongly.

Lyme disease serology may be considered if clinical data suggest that the patient had untreated Lyme disease. However, the history, rather than laboratory testing, drives the diagnosis in Lyme disease.

Genetic testing

In patients with familial ALS, genetic testing may be requested after appropriate counseling. The results of genetic testing may affect not only the patient, but family members as well.

Tests for the SOD1, TARDBP (coding for TDP-43), FUS, ANG, C9orf72, and FIG4 genes, as well as for the gene causing Kennedy disease, are available commercially. Patients with other forms of familial ALS may be referred to receive further information from centers with a research interest in familial ALS.

Brain or spinal MRI may be done to rule out structural lesions and neurologic conditions that sometimes account for early clinical features seen in patients suspected of having ALS (eg, multiple sclerosis, brainstem strokes, tumors, spinal radiculopathy). Results of these studies generally are normal in patients with ALS.

Magnetic resonance spectroscopy may also be used, but it has a high false-negative rate. CT scanning with myelography may be needed in patients in whom an MRI cannot be performed safely (eg, because of the presence of a pacemaker, an implantable defibrillator, or metal fragments).

The value of positron emission tomography (PET) scanning and functional MRI in ALS is being investigated. Imaging studies may not be necessary in patients presenting with advanced disease.

ALS typically progresses within the area first affected and then to adjacent, contiguous regions. As it progresses, patients’ function and independence diminish. When respiratory muscles are affected, patients may be supported using noninvasive or invasive measures. The majority of patients die of ventilatory failure, most having chosen not to opt for long-term invasive mechanical ventilation. Less than 5% of patients die of other causes, such as a heart attack, a serious infection, or blood clots that migrate to the lungs.

The pace of disease progression varies from patient to patient, and the symptoms depend on the muscles affected. Regular monitoring of the patient’s course assists in directing treatment.

Standardized assessment of patients with ALS was facilitated by the development of the ALS Functional Rating Scale, a 10-item standardized questionnaire.[170] It was revised to give greater weight to respiratory involvement and became the 12-item ALSFRS-R,[171, 172] which is used extensively.

In the ALSFRS-R, functions mediated by cervical, trunk, lumbosacral, and respiratory muscles are each assessed by 3 items. Each item is scored from 0-4, with 4 reflecting no involvement by the disease and 0 reflecting maximal involvement. The item scores are added to give a total.

Total scores reflect the impact of ALS, as follows:

• >40 (minimal to mild)

• 39-30 (mild to moderate)

• < 30 (moderate to severe)

• < 20 (advanced disease)

For an individual patient, loss of only 8-10 points on the ALSFRS-R may have severe implications; eg, if respiratory or bulbar function bears the brunt of the losses. A minor limitation of the scale is that it has a floor effect in terms of measuring disease progression in quadriparetic, ventilator-dependent patients.

Most physicians caring for patients with ALS use a measure of the patient’s breathing ability to follow the course of their disease. In the United Kingdon, a governmental clinical guideline exists for monitoring respiratory weakness, with clear points for referral or intervention.

Of the tests of pulmonary function, vital capacity is used most commonly. Additional measures, such as maximal inspiratory and expiratory pressures, arterial blood gas measurements, and overnight oximetry, may provide earlier evidence of dysfunction. Comparison of vital capacity in the upright and supine positions may also provide an earlier indication of weakening ventilatory muscle strength.

Treatment of amyotrophic lateral sclerosis (ALS) may be divided broadly into the following:[19, 173, 174]

• Patient education

• Mechanism-specific treatment

• Adaptive or supportive treatment

Patient education can be enhanced by referral to multidisciplinary clinics staffed by specialists with special interest in ALS, by educational materials prepared for patients and families by national organizations in the United States[175, 176] and other countries or by individual experts,[19] and by patient participation in local support groups.

Outpatient care

Most of the care of patients with ALS may be delivered in the outpatient setting. Often, guidance can be provided by a neurologist, physiatrist, or palliative care physician with special interest in the disease.

Multidisciplinary clinics can provide "one-stop shopping", allowing patients to receive all assessments and recommendations in the course of a single visit; most of these clinics provide a combination of on-site and off-site services. In the United States, Muscular Dystrophy Association/ALS centers and ALS Association certified centers have been established at several major medical centers, and in the United Kingdom, the Motor Neurone Disease Association has a network of 18 accredited Motor Neuron Disease Care and Research Centres.

While multidisciplinary clinics are a highly effective method of delivering care to patients with ALS, this approach may not be available in all venues, because of inadequate patient volume or, in some cases, insufficient philanthropic support. Some patients find full-day assessments exhausting; for them, more frequent, but shorter, visits are more acceptable.

In other models of care, the multidisciplinary team works in the community and visits the patient at home or care is provided through a local hospice team. Primary care providers have an important role and in some settings may be able to coordinate all of the care for a patient with ALS.

Inpatient care

Inpatient care may be needed temporarily for patients with ALS who decompensate in the outpatient setting (eg, because of pneumonia). Hospitalization may also be necessary for patients who reach critical ventilatory failure without having appropriate ventilatory support in place or without having made end-of-life decisions (advance directives) declining such ventilatory support and electing for comfort measures instead.

Riluzole

The glutamate pathway antagonist riluzole (Rilutek) is the only medication that has shown efficacy in extending life in ALS. Compared with placebo, riluzole may prolong median tracheostomy-free survival by 2-3 months in patients younger than 75 years with definite or probable ALS who have had the disease for less than 5 years and who have a forced vital capacity (FVC) of greater than 60%.[177]

Studies

This conclusion is based on 2 double-blinded, randomized, placebo-controlled clinical trials.[33, 34] A third clinical trial, in patients who were ineligible to participate in the second pivotal clinical trial, did not show efficacy, possibly due to low power (small number of patients included relative to the magnitude of the possible effect).[34, 178] A fourth clinical trial, conducted in Japan, did not show efficacy; details of the study’s results have not been published in the English literature.[179, 180]

A Cochrane review that pooled data from the first 3 clinical trials reported that the addition of data from the third trial, which included patients who were older and more seriously affected, reduced the overall treatment effect seen in the first 2 trials.[177] Nevertheless, evidence of benefit from riluzole remained statistically significant.

Subsequent reports have claimed greater efficacy for riluzole in clinical practice than in the clinical trial. However, the relevance of these claims has been challenged[181] because the reports pit class IV evidence against class I evidence, which is contrary to the usual evidence-based approach used to judge treatment efficacy.

Prognosis

Patients with ALS who have depression, frontotemporal dementia (FTD), or a milder level of frontal impairment are now recognized as less likely to accept treatment recommendations and have a poorer prognosis. However, although failure to accept riluzole treatment is a risk factor for poor survival, it is not the cause. Furthermore, registries in place since before the introduction of riluzole show no overall extension of survival of patients with ALS.

Adverse effects

The principal clinical side effects some patients with riluzole may experience are stomach upset and asthenia (lack of energy). These problems resolve if the medication is discontinued.

Cases of interstitial lung disease, some of them severe, have been reported in patients treated with riluzole; many of these cases have proved to be hypersensitivity pneumonitis. If respiratory symptoms such as dry cough and/or dyspnea develop, chest radiography should be performed, and if findings suggest interstitial lung disease or hypersensitivity pneumonitis (eg, bilateral diffuse lung opacities), riluzole should be discontinued immediately. In most reported cases, respiratory symptoms resolved after drug discontinuation and symptomatic treatment.

Aminotransferase

Some patients on riluzole develop abnormal liver function test results or neutropenia. Serum levels of aminotransferases, including alanine aminotransferase (ALT), should be measured before and during riluzole therapy, with ALT levels being evaluated every month during the first 3 months of treatment, every 3 months during the remainder of the first year, and periodically thereafter.

Serum ALT levels should be evaluated more frequently in patients who develop elevations. Treatment should be discontinued if ALT levels reach 5 times the upper limit of normal or higher or if clinical jaundice develops.

Edaravone

In May 2017, the pyrazolone free radical scavenger, edaravone (Radicava), was approved to slow the functional decline in patients with ALS. Although the precise mechanism by which edaravone works in ALS is unknown, it may lessen the effects of oxidative stress, which is thought to be a probable factor in ALS onset and progression.

FDA approval of edaravone was based on the pivotal Phase 3 study (MCI186-19), which evaluated 137 people with ALS. Data demonstrated patients who received edaravone for 6 months experienced significantly less decline in physical function (33% reduction or 2.49 ALSFRS-R points; p=0.001).[182]  

Since then, an oral formulation of edavarone has shown bioequivalence to the IV-administered medication, and it was approved by the FDA in May 2022.[243]

Edaravone has not been approved in Europe, based in part on concerns that short-term efficacy had been demonstrated only in a small, highly selected subgroup of patients, but not in a more broadly selected group, whereas approval was being requested for all patients with ALS. Two phase III clinical trials to evaluate the efficacy and safety of oral edaravone in patients with ALS are ongoing in Europe.

Sodium phenylbutyrate/taurursodiol 

The FDA approved sodium phenylbutyrate/taurursodiol (Relyvrio) in September 2022. The precise mechanism is unknown. Sodium phenylbutyrate is a histone deacetylase inhibitor shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress. Taurursodiol recovers mitochondrial bioenergetics deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the cell’s apoptotic threshold. 

Studies

The phase 2 CENTAUR trial (n = 89 treatment; n = 48 placebo) showed patients treated with sodium phenylbutyrate/taurursodiol had slower progression of disease compared with those randomized to placebo. Also, the ALS functional rating scale revised (ALSFRS-R) score showed the highest score preservation in fine motor skill subscales.[183]  

The open-label extension (OLE) of the CENTAUR trial included 56 participants from the treatment group (ie, early start group) and 34 from the placebo group. Among the early start group, the risk of any key event was 47% lower (p = 0.003). The risk of death or tracheostomy or permanent assisted ventilation was 49% lower in the early start group (p = 0.007). Also, first hospitalization was 44% lower in this group (p = 0.03).[184]   

Median survival in the early start group was 25 months compared with 18.5 months for the group starting treatment in the OLE.[185]   

Tofersen

The FDA granted accelerated approval for tofersen (Qalsody) in April 2023 for treatment of adults with ALS who have a mutation in the superoxide dismutase 1 (SOD1) gene. It is an antisense oligonucleotide that causes degradation of superoxide dismutase 1 (SOD1), which is the second most common and best understood genetic cause of ALS. Tofersen binds to SOD1 mRNA, allowing for its degradation by RNase-H in an effort to reduce synthesis of SOD1 protein production. 

Studies

Accelerated approval was based on data from the 28-week phase 3 VALOR study, which compared the efficacy and safety of tofersen (n = 72; 21 with faster progression) to placebo (n = 39) in adults with ALS and a documented SOD1 mutation. Of these patients, 95 enrolled in the ongoing open-label extension (OLE) study.  

Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P = 0.97). Results for secondary clinical end points did not differ significantly between the 2 groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort.[186]   

Limb stiffness

Limb stiffness can be treated with the antispasticity agents baclofen (Lioresal) and tizanidine (Zanaflex). Baclofen can be started at 10 mg/day and titrated up to 10 mg 3 times per day. If adequate efficacy is not attained at a lower dose, baclofen can be titrated to double that dose, if tolerated. Tizanidine can be started at 1 mg 3 times daily and titrated upward, if tolerated, to as high as 8 mg 3 times daily.

The chief risks of both of these agents are that they induce drowsiness in some patients and that relief of spasticity may result in unpredictable loss of tone and falls. Starting at a low dose permits determination of the patient’s tolerance of the medication, before titration to an effective dose.

Intrathecal baclofen may be considered in slowly progressive, upper motor neuron (UMN) ̶ predominant patients with ALS or in patients with primary lateral sclerosis (PLS), who do not respond adequately to oral treatments.

Sialorrhea

Antisialorrhea treatments include the following:

• Anticholinergics

• Sympathomimetics

• Botulinum toxin type B (potentially hazardous)

• Salivary gland irradiation

Anticholinergics such as amitriptyline (25-50 mg at bedtime) and trihexyphenidyl (Artane; 0.5-2 mg as needed) may be administered as tolerated. A scopolamine patch may work in patients who have not attained adequate relief from oral anticholinergics. Sympathomimetics such as pseudoephedrine may be tried if tolerated; 30-60 mg may be administered as needed or 120-240 mg/day of the extended-release formulations may be used.

The efficacy of injections of botulinum toxin type B (2500 U) into the salivary glands has been reported in a small, double-blinded, placebo-controlled trial[188] , but there is a concern that the toxin could spread to bulbar or respiratory muscles, and there is a manufacturer’s warning to that effect. Salivary gland irradiation (7.5 Gy) was found to effective in a case series with a standardized outcome measure[189] and does not carry the same risk as botulinum toxin.

Thickened secretions

Mucolytics such as guaifenesin may be used to thin thickened secretions, although removal of secretions may require mechanical suction devices. Adequate hydration and humidification of room air may prove helpful and are recommended.

Depression and anxiety

For treatment of depression, selective serotonin reuptake inhibitors (SSRIs), such as citalopram 10-40 mg/day, work best. If the desired benefit is not achieved with one agent in this class, another may be tried.

For anxiety, lorazepam is commonly used (0.5-1 mg prn). Careful titration is required, as benzodiazepines have the potential to cause respiratory depression.

Pain

Pain may occur in patients with ALS as a secondary consequence of immobility, loss of muscle protection of joints, loss of muscle and fat padding of bony prominences, and overexerted muscles. Nonpharmacologic measures to protect bony prominences (cushions and appropriate bed padding) and support overexerted muscles (neck support, trunk support) should be pursued. Range-of-motion exercises should be employed to prevent frozen shoulders.

If pain develops, its causes need to be assessed and appropriate treatment initiated. Often, nonsteroidal anti-inflammatory drugs (NSAIDs) suffice. If needed, they should be prescribed on a regular schedule.

If stronger analgesics are required, tramadol (Ultram), ketorolac (Toradol), morphine (immediate or extended release), or a fentanyl patch may be considered. (Respiratory depression may occur with opiates.) Careful titration, starting with low doses, is needed. Patients must be assured that they will not be in pain as a result of the disease or its secondary consequences.

Cramps

Cramps are difficult to treat. Quinine sulfate was used in the past; the recommended dose for nocturnal cramps was 200-300 or 324 mg at bedtime. However, quinine does not have FDA approval for this indication, its efficacy compared with placebo has not been well established, and there is a concern regarding its potential adverse cardiac effects. Quinine sulfate is contraindicated in patients with a prolonged QT segment, and has many interactions with other drugs. Its clearance is reduced in patients with renal failure.

Other agents that may be tried for treatment of cramps are benzodiazepines, antispasticity agents, and anticonvulsants (eg, gabapentin, carbamazepine, phenytoin). These agents have not been tested for this indication in controlled studies or approved for it, and their efficacy is uncertain.

Incontinence

Urinary urgency may be treated with tolderodine (Detrol). However, the effectiveness of this agent for incontinence may be limited when the incontinence is due to weakening of the muscles of the pelvic floor.

Sleeping problems

When patients complain of sleeping difficulties, the first step is to determine whether these are due to ventilatory failure; this can be accomplished through overnight polysomnography. In some cases the integrity of sleep can be restored just by introducing noninvasive ventilatory support, which usually consists of bilevel positive airway pressure (often with a backup rate). Adjunctive medications may be considered, but the clinician must bear in mind that some drugs may suppress the respiratory drive (hence the need to initiate noninvasive ventilatory support first).

Loss of appetite

Appetite tends to be reduced as ALS progresses. The following reasons have been imputed:

A full stomach makes it harder to breathe

Breakdown of muscle releases amino acids that produce a false sense of satiety

Metabolism of carbohydrates produces CO2, which requires breathing effort to clear

Reduced activity requires less energy intake

Appetite tends to be lost with reduced intake, creating a vicious circle

Nutritional consultation is advised. Frequent small meals, foods rich in fat and protein, and sometimes a feeding gastrostomy are needed. When initiating supplemental feedings in a patient who has not been nourished adequately, attention should be given to ventilatory support, as the patient may be too weak to blow off the extra CO2 or to breathe against a full stomach.

Noninvasive ventilatory support has been shown to improve patients’ quality of life and to extend life when applied as patients begin to experience the early effects of ventilatory failure, including sleep disruption. Noninvasive ventilatory support is probably more effective than all other treatments for prolonging life in ALS patients.

Overnight polysomnography may identify disruption of the contiguity of sleep, one of the early consequences of ventilatory failure that may precede frank apneas, hypopneas, or nocturnal oxygen desaturation.

• Invasive ventilatory support, requiring tracheostomy, may be considered in the following cases:

• Patients who present with respiratory failure and who are otherwise largely neurologically intact

• Patients who want to be kept alive using long-term invasive ventilatory support as their disease progresses

• Patients in whom secretions cannot be managed, and who therefore cannot benefit from noninvasive ventilatory support (this occurs very rarely)

The patient’s appetite tends to decline as the disease progresses, and his/her ability to swallow may become impaired. Consultations with a dietician or nutritionist and with a speech therapist may be requested to help the patient compensate for these losses. Dietary supplements may be used to assure adequate caloric intake.

Placement of a feeding gastrostomy may be considered in patients who cannot maintain adequate caloric intake as a result of swallowing difficulties and who have an FVC of greater than 50% of predicted. A gastrostomy can be placed even in patients with an FVC of less than 50% of predicted, but it requires extra care – usually anesthesiology presence. Consultation with a gastroenterologist or surgeon may be requested if PEG placement is being considered.

Initially, no activity restriction is necessary. Indeed, early in the course of ALS, encourage patients to continue routine activities. However, patients should not overexert themselves to the point of fatigue or pain.

Patients should maintain a regular exercise regimen if their degree of weakness allows. They need to realize, however, that their muscle reserve will diminish before overt sustained weakness appears, which means that in most cases they should avoid extreme endurance exercises (repetitions). Patients with slowly progressive disease will be able to tolerate exercise and benefit from it more than patients with rapidly progressive disease.

The chief goals of activity are as follows:

• Maintenance of range of motion of all joints

• Prevention of painful contractures

• Maintenance of tone and strength of muscles not yet or minimally affected by the disease

• Maintenance or improvement of cardiovascular health, mood, and energy level (this can be accomplished with low-impact exercise)

As the disease progresses, patients may become unstable and at risk of falls and may need to be counseled to use assistive devices or to not transfer without appropriate support. If they reach a point at which they cannot manage a vehicle safely, including in emergencies, they need to be counseled to stop driving or have modifications made to the car so that they are able to drive safely.

In the United States, some states require mandatory reporting by practitioners to the Department of Motor Vehicle Affairs, and some require disabled patients to pass a driving assessment if they have modifications made to their car (eg, hand controls). In the United Kingdom, any medical condition likely to last more than 3 months requires reporting to the Driver and Vehicle Licensing Agency by the patient.

Many patients with ALS elect to try alternative therapies. If not unsafe or exorbitantly priced, these treatments may be a reasonable approach to giving patients a sense of some control, may confer on them a feeling of calm, and may thus be of benefit, in subjective terms. Since most, if not all, alternative therapies have not been tested against placebo controls, physicians cannot provide blanket recommendations but may be able to be supportive, if circumstances permit, of specific patient choices.

When alternative therapies impose a great burden on patients, in terms of cost or time commitment, they should be avoided. Since 2009, the ALS Untangled group of investigators, who are members of the North American ALS Research Group or the World Federation of Neurology (WFN) ALS Research Group, has evaluated several claims of efficacy of specific alternative therapies (to slow the course of ALS) and shown them to lack adequate foundation.

Doing this properly requires time, motivation, adequate staff, and preparation. The American Academy of Neurology (AAN) 1999 Practice Parameter[173] provided the following suggestions for breaking the news of a diagnosis of ALS to a patient, based on a review of literature pertaining to other diseases:

• Give the diagnosis to the patient and discuss its implications; respect the cultural and social background of the patient in the communication process by asking whether the patient wishes to receive information or prefers that the information be communicated to a family member

• Always give the diagnosis in person, never by telephone

• Provide printed materials about the disease, as well as contact information for advocacy associations (providing a written summary or audiotape summarizing what has been discussed was suggested, but this author believes that this option needs to be exercised primarily in the absence of adequate printed material)

• Avoid withholding the diagnosis, providing insufficient information, delivering information callously, or taking away or failing to provide hope

In this era of readily available information on the Internet, provision of the diagnosis will generate independent activity on the part of patients, families and friends to educate themselves about the disease. Thus, it is helpful if clinicians point patients and the families to those resources that they feel will serve this purpose best, to serve as the starting point (see Patient Education).

The 2009 AAN update to the 1999 practice parameter[2] refers to a 6-step protocol, described by the acronym SPIKES, that was designed for delivering bad news to patients with cancer.[192] The following is summarized from Appendix e-1:[2]

• Setting - Establish the appropriate setting

• Perception - Determine the needs and the perception of the patient

• Invitation - Request an invitation to give the news

• Knowledge - Provide knowledge (information) to the patient

• Explore/Empathic - Explore the patient’s feelings with empathic responses

• Summarize/Strategy - Summarize and form a strategy with the patient with which to go forward

The SPIKES protocol has several advantages and may be further improved by the following 3 measures. First, it is important that relevant family members be present when the patient is informed about the diagnosis, so that the patient is not the one who has to inform them and answer their questions. They can support the patient, and the neurologist can inform and support them directly.

Second, it is very helpful to schedule an early follow-up visit to answer questions that will arise and inform/update family members who were not present when the diagnosis was given. Many patients and families will not remember most of what they are told when they hear the diagnosis for the first time, as they will be in shock. The shock may be less if they have anticipated the bad news, but it cannot be avoided completely. The greater the perceived shock, the more the focus should be on support and discussing the next steps, including the follow-up visit.

Third, it is helpful to have a handout summarizing the information presented in the clinic. The handout should provide links to appropriate Web sites, as many patients will want to take an active role in educating themselves with the use of these resources.

The patient and his/her family may want to tarry a while after the visit. It is helpful to have a nonphysician staff member available to support them and to reinforce the immediate next steps.

Support groups are available to patients in many communities. Burnout of the primary caregiver needs to be anticipated and avoided by assuring that the primary caregiver is not the only caregiver.

Clinical trials

Patients with ALS may wish to help with the search for treatments for the disease through participation in clinical trials. They should be encouraged to focus on trials that have been listed with the ALS Association, the Muscular Dystrophy Association (MDA), and ClinicalTrials.gov, which is a registry of federally and privately supported clinical trials conducted in the United States and around the world.

Off-label pharmaceuticals

Patients often request prescription of pharmaceuticals for off-label use in the hope of slowing disease progression. Since double-blinded, placebo-controlled studies to date have shown that all such pharmaceuticals either made patients worse or had no benefit, this practice should be avoided.

Government benefits

In the United States, patients are eligible for Social Security and Medicare benefits once they are diagnosed with ALS, without the waiting period required of other patients with chronic diseases. Patients should be advised to apply early.

Since September 2008, ALS has been considered a service-connected condition for US veterans, and they are eligible for care and benefits.[193] Eligible patients should be advised to apply early. Volunteers from local branches of veterans’ organizations may be able to assist in preparing the application and moving it rapidly through the approval process.

End-of-life considerations

End-of-life issues may be discussed and clarified early. However, this may not work well for some patients. The physician should be aware of the individual state or national laws that regulate these issues; encourage, if appropriate for the patient, completion of advance directives; and document the patient’s preferences in the medical records, whether or not formal advance directives have been written.

Resource access

For patients with limited access to home-based resources, social service professionals may be able to assist with placement. Local branches of advocacy organizations (the ALS Association of America and the Muscular Dystrophy Association) may be excellent sources of information on what resources are available locally.

Legal affairs

Patients will have decreasing ability to sign documents or to mobilize themselves for taking care of personal affairs. Some may benefit from legal advice. The earlier they do so, the better, but they should be allowed to recover first from the initial shock of the diagnosis.

Loss of independence

All patients will become at risk for falls as ALS progresses; they should be informed of this and cautioned gently. Most patients tend to sustain several falls before they relinquish the independent activities that led to them.

All patients will become unable to drive as their disease progresses. They need to be alerted when this draws close. Most are gracious about quitting before their driving results in injury. Some states require mandatory reporting by practitioners to the Department of Motor Vehicle Affairs. In the United Kingdom, patients are obliged to inform the Driver and Vehicle Licensing Agency.

Consultants are best used within the multidisciplinary model based on patients’ preferences and need to complement the range of services that the patients’ primary care providers and primary neurologists, palliative care physicians, or physiatrists can provide directly. The following consultations may prove helpful:

• Physical and occupational therapists help the patient adapt to loss of function, provide exercises to maximize existing function and ameliorate spasticity, identify safety concerns and advise how to address them, and help patients to select and learn to use assistive devices, including, as the disease advances, a customized wheelchair

• A speech therapist can advise on adaptation to swallowing difficulties and, as speech fails, on the use of communication devices

• A respiratory therapist can assist with learning to use noninvasive ventilation support and, if needed, advise on secretion management, suctioning equipment, and selection of a cough assistive device

• A dietician or nutritionist evaluates caloric intake; advises how to optimize it, particularly if intake is declining; and may be able to provide guidance regarding nutritional supplementation

• A pulmonologist, if needed, assesses for tracheostomy and manages the ventilator, tracheostomy, and complications (such as infections) if this treatment is selected

• A gastroenterologist or general surgeon advises and performs PEG placement and advises on its care and maintenance

• Visiting nurses assess patients’ in-home needs and help quantify the need for and time the introduction of personal care assistants (home healthcare aides) and home-based therapies

• Hospice service provides the framework for in-home end-of-life care or helps with alternative arrangements

• Spiritual (religious) services, if elected by patients, usually connect with the resource of their choice

While many patients and families may benefit from referral to a psychiatrist, psychologist, or counselor, patients may be most likely to use these resources if they have already done so prior to disease onset or if these options are offered within the multidisciplinary model of care.

Patients are best cared for in a designated ALS center. Many mechanical aids can help them to overcome disabilities. A patient’s length of survival and quality of life are enhanced by night-time breathing assistance early in the course of the disease and by aggressive application of alternate feeding options to ensure good nutrition once swallowing becomes difficult.[194]

The 2009 AAN practice parameter guideline reviewed available evidence to help maximize the care and quality of life of patients with ALS.[2, 3] The recommendations can be summarized as follows:

• Riluzole should be offered to all patients with ALS to slow disease progression

• Enteral nutrition via PEG should be considered to stabilize body weight in patients with impaired oral intake

• PEG placement when FVC is still greater than 50% predicted minimizes the risk of insertion

• PEG placement probably prolongs survival to some degree

• NIV should be offered to treat respiratory insufficiency in order to prolong survival and slow the decline of FVC

• NIV may be considered at the earliest sign of nocturnal hypoventilation or respiratory insufficiency

• Mechanical insufflation/exsufflation may be considered to clear secretions in patients with reduced peak cough flow, particularly during an acute lower respiratory infection

• Creatine and high-dose vitamin E should not be used

Smoking is the first established environmental risk factor for ALS.[54, 56]  Smoking avoidance may result in a decrease in the age-specific incidence of the disease. However, this presumptive benefit may be attenuated if lower mortality from other smoking-related diseases (eg, cancer, cardiovascular diseases, stroke) results in more patients surviving to be at risk for ALS in each age bracket. As the population lives to older ages (in which age-specific incidence of ALS is higher), the crude incidence of ALS may increase.

Air pollution has been implicated as associated with ALS incidence[225, 226, 227] , as well as that of other neurodegenerative diseases.[224] Reduction of air pollution has the potential to improve health on multiple levels.

Individuals with a gene for familial ALS may benefit from genetic counseling if they wish to minimize the risk of transmitting the gene to the next generation, for example through pregestational diagnosis (PGD).

In October 2009, the American Academy of Neurology (AAN) published a 2-part, evidence-based Practice Parameter update about the care of patients with ALS.[2, 3]  These publications updated the 1999 evidence-based practice parameter.[173]

NIV, PEG, and riluzole

The chief findings of the practice parameter are that for extending life or slowing disease progression, the evidence is best for use of noninvasive ventilation (NIV), percutaneous endoscopic gastrostomy (PEG), and riluzole. The authors comment that these treatments are often underutilized and recommend that they should be offered to patients, in the case of riluzole, or considered by the physician, in the case of NIV and PEG.

The median extension of life by riluzole in placebo-controlled studies was 2-3 months. The median extension of life by NIV or PEG may be approximately 6 months, provided the treatments are applied early and adhered to. The efficacy of NIV is supported by a randomized, controlled trial.[187]

Multidisciplinary care

The authors also recommend that referral to a multidisciplinary clinic should be considered for managing patients with ALS. Such clinics can optimize healthcare delivery, prolong survival, and enhance quality of life.

Botulinum toxin

In patients with sialorrhea that is refractory to treatment with standard medications, botulinum toxin B injection of the salivary glands should be considered. Alternatively, low-dose radiation therapy to the salivary glands may be considered.

Botulinum toxin for ALS carries a manufacturer's warning regarding possible spread of the toxin to ventilatory muscles (leading to exacerbation of ventilatory failure) or bulbar muscles (exacerbating their weakness). The risk of these adverse effects tilts the balance in terms of safety toward salivary gland irradiation, except in patients with exceptional ventilatory and bulbar reserves.

Dextromethorphan and quinidine

Finally, the guideline recommends that dextromethorphan and quinidine be considered for pseudobulbar affect. A combination of dextromethorphan and quinidine (Nuedexta) has shown efficacy in ameliorating involuntary laughter and crying (the expression of pseudobulbar affect).[186, 187]  It has FDA approval for this indication.

Clinician and patient summaries of the AAN guidelines are available on the AAN website:

• Clinician summary

• Patient summary

Four mechanism-based medications are approved in the United States.

The glutamate pathway antagonist riluzole is the first medication that has shown efficacy in extending life in amyotrophic lateral sclerosis (ALS). The American Academy of Neurology (AAN) guideline recommends that riluzole be offered to patients with ALS.[2]  

The pyrazolone free radical scavenger, edaravone (Radicava), was approved to slow the functional decline in patients with ALS.[182]  This medication was not approved by the European Drug Agency, as the efficacy was demonstrated in a small sub-population of carefully-selected patients, and could not be generalized.

The FDA approved sodium phenylbutyrate/taurursodiol (Relyvrio) in September 2022.[183, 184, 185]  

Tofersen, the first treatment to target ALS with a mutation in the SOD1 gene, was approved in April 2023.[186]

Other medications may be useful for relief of symptoms associated with ALS. These include the following:

• Muscle relaxants to relieve spasticity

• The combination of dextromethorphan and quinidine to decrease emotional lability of pseudobulbar affect

• Anticholinergics and sympathomimetics for sialorrhea 

• Mucolytics for thickened secretions

• Lorazepam for anxiety

• Selective serotonin reuptake inhibitors (SSRIs) for depression

• Nonsteroidal anti-inflammatory drugs (NSAIDs), tramadol (Ultram), ketorolac (Toradol), morphine (immediate or extended release), or transdermal fentanyl, for pain

Class Summary

Riluzole is thought to counteract excitatory amino acid (glutaminergic) pathways, noncompetitively block N-methyl-D-aspartate (NMDA)–mediated responses, and inactivate voltage-dependent sodium channels. Its exact mechanism of action in ALS is unknown.

Riluzole (Exservan, Rilutek, Tiglutik)

Riluzole (Rilutek)

Benzothiazole agent that is well absorbed, with average oral bioavailability of 60% and mean elimination half-life of 12 hours; steady state is reached within 5 days with multiple dose administration. Metabolism occurs in the liver (P450-dependent glucuronidation and hydroxylation), with 6 major and a few minor metabolites produced. It is available as a tablet, oral suspension, or oral film that dissolves on the tongue. The recommended dosage for riluzole is 50 mg twice daily. Riluzole is used for extension of time to death or tracheostomy.

Class Summary

Tofersen is an antisense oligonucleotide that causes degradation of superoxide dismutase 1 (SOD1), which is the second most common and best understood genetic cause of ALS. Tofersen binds to SOD1 mRNA, allowing for its degradation by RNase-H in an effort to reduce synthesis of SOD1 protein production. 

Tofersen (Qalsody)

Tofersen is an antisense oligonucleotide that blocks production of mSOD1 in patients with SOD1 ALS. It has been approved by the FDA for patients with SOD1 ALS. It is administered intrathecally into the spinal fluid, via a lumbar puncture. Initially, three doses are given 14 days apart, and then maintenance injections are given every 28 days.  

Class Summary

Several drugs that decrease oxidative stress have been approved by the FDA for treatment of ALS. The precise mechanism by which by which these drugs exerts therapteutic effects in patients with ALS is unknown. 

Edaravone (Radicava, Radicava ORS)

Edaravone is a pyrazolone free radical scavenger; mechanism by which the drug exerts its therapeutic effects in ALS is unknown. It is theorized to decrease effects of oxidative stress, a likely factor in the onset and progression of ALS. Administration is by IV infusion, requiring it to be given by a healthcare professional and monitoring for infusion-related reactions. An oral formulation is also available.

Sodium phenylbutyrate/taurursodiol (Relyvrio)

The precise mechanism of action in patients with ALS is unknown. Sodium phenylbutyrate is a histone deacetylase inhibitor shown to upregulate heat shock proteins and act as a small molecular chaperone, thereby ameliorating toxicity from endoplasmic reticulum stress. Taurursodiol recovers mitochondrial bioenergetics deficits through several mechanisms, including by preventing translocation of the Bax protein into the mitochondrial membrane, thus reducing mitochondrial permeability and increasing the cell’s apoptotic threshold. 

Class Summary

These agents relieve spasticity and muscle spasms in patients with symptoms of limb stiffness.

Baclofen (Lioresal, Gablofen, Lyvispah)

Baclofen is metabolized in the liver and excreted primarily in urine. This agent is not a controlled substance under the Drug Enforcement Administration (DEA).

Class Summary

Alpha2 adrenergic agonists decrease excitatory input to alpha motor neurons (which are a type of lower motor neuron [LMN]). Common alpha2 adrenergic effects include decrease release of acetylcholine and norepinephrine, contraction of sphincters in the gastrointestinal tract, and inhibition of lipolysis.

Tizanidine (Zanaflex)

Tizanidine is a centrally acting muscle relaxant metabolized in the liver and excreted in urine and feces. It is used in patients with predominantly upper motor neuron (UMN) involvement. It is not a DEA-controlled substance.

Class Summary

The combination of dextromethorphan and quinidine is shown to decrease emotional lability of pseudobulbar affect (PBA).

Dextromethorphan and quinidine (Nuedexta)

Dextromethorphan is a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist. Quinidine increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P4502D6, which catalyzes a major biotransformation pathway for dextromethorphan. The mechanism by which dextromethorphan exerts therapeutic effects in patients with PBA is unknown.

This combination is indicated for PBA and symptoms associated with ALS (and multiple sclerosis) that result in involuntary, sudden, and frequent episodes of laughing and/or crying. It is available as a capsule containing dextromethorphan 20 mg and quinidine 10 mg.